Endocrine-Disrupting Chemicals and the Offsprings: Prenatal Exposure

Solerte, Maria Laura; Cosmi, Erich

doi:10.1007/978-3-031-36494-5_9

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Abstract

Over the last 10 decades, the changes in normal environmental conditions, directly or indirectly connected to the presence of several chemical substances released in various ways and means, for many territories, throughout the planet, have become extremely evident, as well as the relative consequences assessed, which involve numerous international working groups. Starting from territorial pollution and known environmental disasters, the World Health Organization, Food and Drug Administration, European Food Safety Authority, European Commission, other international regulatory agencies, scientific societies, and research groups had proposed, through milestone epochs, the methods of study and monitoring of environmentally harmful molecules capable of interfering with the endocrine system, in wildlife, laboratory animals, and humans. Moreover, attention was focused on endocrine functions related to reproductive health and on mechanisms of interaction, during gestation, between fetus, mother, and placenta, in order to bridge the gap of the lack of knowledge in this global theme.

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Prenatal Exposure to Endocrine Disrupting Chemicals and Their Effect on Health Later in Life

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Keywords

9.1 Introduction

The role of environmental impact on humans is extensively studied and evaluated throughout the world, given that numerous correlations between harmful environmental factors and many pathologies had been extrapolated. Following several clinical evidences, numerous research were carried out by study groups; since the late 1980s to early 1990s, the need to monitor the major long-term consequences on human health of exposure to chemical factors capable of altering the endocrine system during life has been underlined. In 1991, during the World Health Organization (hereafter WHO) seminar, topics regarding the impact of the toxic environmental factors on reproductive health (hereafter RH) were extensively discussed by scientists coming from all parts of the world; particularly, they focused on the correlation between harmful environment, pollutants, sperm quantitative/qualitative alterations [1], and reproductive rate/outcome, also with a view to fill the absence of essential notions.

Therefore, the modalities of RH study and surveillance were indicated, also retracing the dramatic events of Seveso 1976, Bhopal 1984, and Chernobyl 1986, and their harmful effects; research and intervention activities were here promoted to define the nature of harmful substances [1]. This era marked the elevation of the issues linked to the environmental modifications, which several countries had to face up in light of the increasing diseases derived from this extremely negative correlation. A great attention had begun to actively focus on global topics such as climate change, alteration of biological diversity, stratospheric depletion of ozone, air transport pollution, acid deposition, and toxic waste. In particular, attention was focused on the nature and mechanism of action of the various environmental factors as the cause of negative influence on the male and female reproductive system, for example, the sperm quantity and quality anomalies, infertility, cell/chromosome pathology, intrauterine growth retardation, prenatal or postnatal death, offspring defects, neurological issues, and early aging, which arose later [1]. Even as early as 1962, a well-documented articulate text, defined as “changing the world,” was introduced as a debated and intricate scientific concept of the interaction between dichlorodiphenyltrichloroethane (hereafter DDT or p,p’-DDT, which is the isomer that has the greatest insecticidal capacity), a powerful lasting chemical pesticide, and health, significantly active on human sexual development and reproduction, which greatly affected public opinion [2]. The uncontrolled use of synthetic pesticides was emphasized; the book was so significant that it inspired the environmental movements that took place in the following years against ambient poisons. Even then, although the evidences of severe, negative, and cancerous pesticide effects were highlighted, they became a controversial and debatable topic. Hence, natural or man-made disaster and/or chemical pollutants began to be blatantly indicated as the main culprits for the negative consequences on humans. Moreover, the research needs for methodologies and surveillance data were explained, especially in order to improve the international works for similar approaches and database, to get alert systems, and to assess the toxic levels of the chemicals indicated. In addition, the need to introduce multidisciplinary studies has emerged, for evaluations of both the environment and cellular processes negatively affected by biological, chemical, and physical factors and pesticide exposure: those damages result in problems related to fertility, spontaneous abortion, womb growth anomalies of the fetus, and various pathologies found at birth, due to the indirect exposure in pregnancy or early stages of extrauterine life [1, 3]. Chemical pollutions, radiation, and various forms of stress could be the main elements worthy of further study in order to increase the knowledge of their interaction with the physiological function of the reproductive system and the early prenatal organogenesis development [3] of the subsequent offsprings and long-term effects [3]. Also, excesses of vitamin A, radiation caused by Chernobyl disaster, and methylmercury, for specific neurological defects, were cited [1]. Some harmful chemical substances, including industrial ones, released in the ambient, starting from the World War II [1,2,3], were also listed, for example, pesticides (later also biocides), fungicides, metals, insecticides, and nematocides, provided with the ability to bind to the receptors for steroid hormones situated in specific target cells and tissues, therefore simulating their action. With increasing relevance for the control of the conditions necessary for general health, the well-documented concept was formed about the negative interference of polychlorinated biphenyls (henceforth PCBs), DDT, other pesticides, and their metabolites. With the knowledge gained in that historical period, some studies had emerged, to spread greater long-term awareness as well as health consequences associated with the exposure to chemicals that disrupt the endocrine system during the breastfeeding (for the bioaccumulation of toxic substances) and the first years of life and, therefore, to assess the related lifelong health risks. Some evidence has been exposed that pollutants found in rainwater, well water, lakes, and oceans, as well as freshwater and marine food products, can interfere with the endocrine development in wild and laboratory animals or humans. Furthermore, hundreds of synthetic elements, some with the agonist, antagonist, and synergist abilities as endocrine disruptors, disseminated in the ambient, were identified: their capacity to negatively affect development functionality of both the immune and endocrine systems was pointed out [3]. The production of oocytes, pregnancy, and lactation time are phases of female life that can cause the mobilization of toxic environmental molecules accumulated in the fat tissue and therefore can give rise to the phenomenon of transgenerational exposure [3]. Starting from the consolidated concept that, in mammals and other vertebrates, the connections between cells are indispensable for their physiological development, the embryology science had begun to orient itself on studies of substances produced by a group of cells that synthesize a product, which then influences the course of development determining the regular function of other cell units. Groups of hormones have been identified, derived from mother’s ovaries, adrenal glands, placenta, fetal gonads, and adrenal glands, with a primary regulation role in many tissues’ development. Moreover, the type of organs in the offsprings of subjects exposed to toxic substances had therefore been identified, who could have been more affected by the adverse consequences; the presence of receptors, also in the fetal life, for ovarian, testicular, placenta, and adrenal steroid hormones made the reproductive system one of the main targets [3]. Indeed, it is known that at the end of the second month of pregnancy, highly sensitive stages of growth are identified, regulated by steroid hormones indicated above [3, 4]. Prior to 1980s–1990s, over the past 30–50 years, some authors have argued about the correlations between abnormalities of the male genital tract, decrease of semen volume and sperm counts, and mothers’ intake of synthetic estrogens during their gestation: the association with diethylstilbestrol (hereafter DES) was also mentioned, which is a synthetic estrogen discovered in 1938 and used from 1945 to 1971 [3, 4] to prevent spontaneous miscarriage [3], and the major increase in the incidence of hypospadias, cryptorchidism, and testicular cancer [5]. This theory was born from the concept that the latter three pathologies, mentioned above, could have the same etiological factors involved in the male fetal life.

In addition, DES was named as a “mother substance,” due to its powerful estrogenic capacity as well as its effects; DES exposure was followed as an estrogen agonist model to analyze the impact of substances with equal potential for estrogenic endocrine disruption [3]. Moreover, in order to understand the route and mechanism of access of the estrogens (endogenous/exogenous) and therefore of their harmful action, it was reported that the physiological hormone, by an enterohepatic recirculation, was metabolized and reabsorbed by the bowel, more easily when the bowel contained low amounts of fiber. This last aspect, formulated as hypothesis, could explain the lower incidence of breast cancer, estrogen linked, in women on a high-fiber diet, which conferred some sort of protection right against estrogen [5]. This above assumption has allowed to expand the research and knowledge also on subsequent synthesis molecules and on their overexposure effects on the development of reproductive traits and related disorders [5]. Previously, other authors also published the adverse effects of DES [6], affecting the male and female reproductive tract; the pathological forms had been well listened: defects of vagina-cervix-uterus-fallopian tubes, adenosis, clear cell adenocarcinoma, breast cancer for female subjects, and testicle hypoplasia, cryptorchidism, microphallus, and ependymal cysts for the male ones; later, these anomalies led to dysfunction in reproductive age and pregnancy time. As known, DES was banned as drug for pregnant women, by the Food and Drug Administration (hereafter FDA), in 1971, and for meat production in 1979 and in 1978/1981 in Europe [3, 5]. Moreover, the effects of cigarette smoking were addressed; not least in importance but only for narrative scheme, already before 1976, the issue of smoking in pregnancy had been examined, revealing that fetal growth retardation, linked to birth weight under 2.500 g, exhibited in two somatic types: the first with a low ponderal index and the second one with short crown-heel length for fetal age [7]. The reduction of the average body length for dates of full-term births from smoking mothers had speculated that the use of cigarettes was associated with the second type of growth retardation [7]. Given the evident correlations, continuously published, between causes and effects, several policies of careful monitoring were initiated, extended, continuously used, and updated, with the aim of identifying and regulating the numerous chemicals present in the environment responsible for the endocrine alteration effects, also with long-term problems. Indeed, even that time, the major danger for the physiological functions of the reproductive system seemed to be chemical pollutants [8]. Furthermore, epidemiology science, based on precise and systematic data takeover, could already identify diseases and their related risk factors and try to develop adequate prevention strategies [8]. To better understand the various deleterious components that negatively affect important physiological body functions, it might be interesting to review some definitions [8].

9.2 Identification Overview

9.2.1 Endocrine Glands and System

The univocal definition of the endocrine system is, for a broad view, the union of the balanced interdependent body glands (Fig. 9.1), including hypothalamus, pituitary, pineal, thyroid, pancreas, adrenal, gonads, and fat tissue, distant for topographical and physical connections, with internal secretion.

A schematic illustration of the endocrine system. It shows the entire human body with the glands around it. The glands are anterior and posterior view of the parathyroid glands, thymus, adrenals, ovary, pregnancy from conception to implantation, testis, fat tissue, pancreas, anterior and posterior views of the pituitary, hypothalamus and pineal gland. — **Fig. 9.1**

This system is basilar for the control, regulation, and coordination of several human usual tasks as development, sleep, homeostasis, immunity, metabolism, growth, response to stress or injury stimulations, behavior, sexual functions, and reproductive processes; it has very specific functions and complex interactions with the physiology of the human body and its hormonal targets. The endocrine system interacts, in a complementary and bidirectional sense, with the nervous system which, however, differs from the first one for the greater speed of signal transmissions [9, 10]. The endocrine structure organs are essential to maintain organic homeostasis, also when external conditions vary; the system is provided with dense vascularization (Fig. 9.2a) [9], extremely sensitive to changes by aging and pathologies [9]. Therefore, endocrine unit has been identified as a refined and, at the same time, complicated and effective network, also equipped with vascular niches, of connection between their three main components: endocrine glands, hormones, and receptors. This elementary scheme is a prerequisite for understanding the multiple mechanisms of the endocrine system, in constant balance, which is responsible for organizing, influencing, and controlling several human functions, mainly guided by the hypothalamus-pituitary axis, which is a neuroendocrine organ essential for regulating growth and development [9]. The endocrine system can be affected by disorders that can alter the normal balance of human body functions and cause adverse health effects; individuals are constantly exposed to a wide range of substances, which cause a negative impact on endocrine products, in several contexts such as work, drug or consumer product use, and even natural resources. Furthermore, the aging effects on the endothelial cells of the vascular niches have been reported in detail, identifying it as a vascular microenvironment that governs the function of cells and subtypes (Fig. 9.2b) [9].

Two schematics. a provides a visual representation of the vascular niche functions in the endocrine system such as thyroid, pituitary, adrenal glands, ovary, testis, and pancreas. b illustrates the vascular niche function in the endocrine system for young and aged. It represents the impact of aging on E Cs and their secretion of angiocrine signals. — **Fig. 9.2**

9.2.1.1 Glands

The endocrine glands (hereafter EGs), called also “specialized ductless glands” due to their characteristic functional capacity, are highly vascularized (Fig. 9.2a) [9] tissues or organs, equipped with internal secretion mechanism and cellular/molecular cues, that signal each other in pulsatile, sequence, and feedback patterns. Their dense vascular systems are in turn a “microenvironment” [9] and are formed by endothelial cells (hereafter ECs) that also play an endocrine role, by changing the vascular diameters, and vascular endothelial growth factor (hereafter VEGF), which plays roles in angio-vasculo-morphogenesis: ECs, microenvironment vessels, and their roles are shown in Fig. 9.2a, b [9], with the related sophisticated circuits linked to the main endocrine organs. The EGs are located in various anatomic districts of the human body and have peculiar capacities to synthesize chemical messengers, called hormones, released directly into the blood circulatory system, unlike the exocrine glands, which hence carry their products up to the target organs all over the body. Thanks to the rich vascular systems, there are rapid interactions between productive cells and the endothelium and its ECs. The EGs have different anatomic, histological, morphological, and functional characteristics; as the main pattern, they are vascular and commonly have intracellular vacuoles or granules that store their hormonal products [10].

As mentioned above, the endocrine system, and therefore the EGs, also suffers from the effects of aging, as shown, for instance, by the development of the reactive oxygen species (hereafter ROS), from altered mitochondrial work (Fig. 9.2b) [9]. The entire endocrine system is made up of an elaborate network of EGs and axes, provided with feedback, negative or positive, working by circadian rhythm or pulsatile model, and, precisely, comprises the following main elements (Fig. 9.1) [9, 10]:

1.
Hypothalamus: It is a smart essential control coordinating center, located deep in the center of the brain; through its paraventricular nucleus neuroendocrine, it can control homeostasis, pituitary gland, blood pressure, energy, water balance, mood, appetite, reproductive behaviors, temperature, and stress. It produces corticotropin-releasing hormone (hereafter CRH), thyrotropin-releasing hormone (hereafter TRH), growth hormone-releasing hormone (hereafter GH-RH), somatostatin-releasing hormone (hereafter SRIH), gonadotropin-releasing hormone (Gn-RH), luteinizing hormone-releasing hormone (hereafter LH-RH), prolactin-releasing peptide (hereafter PRH), and prolactin-releasing/inhibitor factor (hereafter PRF/PIF). Hypothalamus is the main component of the neuroendocrine system with the interaction of (x) hypothalamus-(anterior) pituitary-adrenal axis (hereafter HPA), (xx) hypothalamus-(anterior) pituitary-thyroid axis (hereafter HPT), (xxx) hypothalamus-(anterior) pituitary-gonadal axis (hereafter HPG), and axis-relative feedback reactions.
2.
Pituitary gland: Named also hypophysis, it has anterior/adeno and posterior/neuro lobes located in the brain, at the base of the hypothalamus, and is “the most highly vascularized mammalian tissue” [9]; it is an essential control center, via its anterior lobe endocrine cell hormones, of the other endocrine glands and several body functions as metabolism, blood pressure, stress, growth reproduction, labor, lactation, and water balance. Hypophysis produces thyroid-stimulating hormone (hereafter TSH), adrenocorticotropic hormone (hereafter ACTH), follicle-stimulating hormone (hereafter FSH), and luteinizing hormone (hereafter LH). This gland is an integral part of the HPA, HPG, and HPT axes.
3.
Pineal gland: Named also epiphysis cerebri, it is located in the epithalamus brain zone, behind the hypophysis; it produces a hormone that regulates sleep, puberty, circadian rhythms, and other functions; in particular, it obtains retina information on the light-dark cycle from the external ambient and uses these data to rhythmically synthesize and secrete, by pinealocytes, its hormone called melatonin (tryptophan-serotonin derived).
4.
Thyroid gland: With its left and right lobes, it is located on the anterior side of the neck, in front of the trachea and larynx; it mainly regulates the metabolism through its hormones and the feedback of the HPT axis. Thyroid gland produces two hormones: thyroxine (hereafter T4) and triiodothyronine (hereafter T3).
5.
Parathyroid glands: These are four small glands located on both sides of the thyroid, posteriorly, but their activities are unrelated; they control, through the production of parathyroid hormone parathormone (hereafter PTH), calcium level regulation, bone structures, and the body’s calcium balance; moreover, PTH involves the kidney and small intestine activities.
6.
Thymus: With its two small lobes, it is a primary organ of the lymphatic system, located on the upper front side of the chest, between the lungs, behind the sternum, below the sternum manubrium, in action before birth until puberty to produce T-lymphocytes; this gland goes to a progressive involution during the human aging. Thymus produces an array of hormones, like thymosin, thymopoietin, thymic humoral factor, and thymulin, regulating the nervous-endocrine circuits and the immune cell production. Thymus is a hub between the endocrine-immune-nervous interdependent systems, also equipped with a feedback mechanism (thymus as regulator of HPG axis).
7.
Adrenal glands: With their subzones (cortex and medulla), they are located on the top of both kidneys, in the retroperitoneum; they regulate blood pressure, electrolyte balance, immune response, stress reaction, metabolism, and salt and water balance; some of their functions/steroidogenesis also regulate HPA axis, of which it is a component. Adrenal cortex and medulla produce (a) the corticosteroids cortisol and aldosterone, (b) the catecholamines adrenaline/epinephrine and noradrenaline/norepinephrine, (c) corticotropin-releasing hormone (hereafter CRH), (d) dehydroepiandrosterone (precursor for male/female sex hormones, hereafter DHEA), and (e) antidiuretic hormone named vasopressin (hereafter ADH).
8.
Pancreas: It is located across the back of the abdomen: its endocrine cells and subtypes (almost 1–2%, of the entire organ, clustered in islets) regulate blood glucose levels by insulin and glucagon hormone production and secretion.
9.
Placenta: It is a fetal annex located into the maternal womb, derived from the early fusion of chorion and allantoid in the precocious stage of gestation; at the same development time, in the very early time of pregnancy, the syncytio/cytotrophoblast cells synthetize (a) the chorionic gonadotropin glycoprotein hormone (hereafter hCG), (b) progesterone, (c) a group of estrogens (estrone, 17β-estradiol, estriol, esterol (hereafter, respectively, E₁, E₂, E₃, and E₄), (d) human placental lactogen (hereafter hPL), and (e) human placental growth hormone (hereafter hPGH), which are fundamental for gestation. It is an essential endocrine gland, thanks to its hormones, during pregnancy for itself, the mother, and the fetus; other hormones are linked to the placental functions [11].
10.
Ovaries: With their three zones, they are located on both sides of the uterus; they are the female reproductive unit by production of follicles, oocytes, and corpus luteum cells via their main steroid hormones, estrogen, progesterone, and androgens. These glands are an integral part of the HPG axis, necessary for fertility and breast growth.
11.
Testes: With their two zones, they are located behind the penis; they are the male reproductive unit by sperm and testosterone hormone production. Also, the endothelium has endocrine function by its ECs, which release vasoactive signals for vasodilatation or vasoconstriction. Through the feedback, they influence the hypothalamic-pituitary axis.

Other organs own secondary endocrine functions, including bones, kidneys, fat tissue, liver, and heart. Thanks to the hormones produced, EGs can exert control of most of the bodily functions: mood, emotions, sexual function, reproduction, sleep, metabolism, growth, and others; their functionality is interconnected with the link of microvasculature and ECs [9, 10]. To define the origin of the functional anomalies, which also occur when a mechanism step of these glands does not work as it should, and therefore to treat them to restore their interface with the reproductive mechanisms, the pathophysiology and the endocrine clinic of human reproduction have emerged as dedicated medical branches. Moreover, it has also become possible to understand the importance of the physiological and necessary correct functioning of the endocrine glands and the metabolic control of adipose tissue, liver tissue, and other units, in turn regulated by adrenaline, noradrenaline, and insulin; the renal functions checked by angiotensin and renin; and the sex differentiation and growth regulated by sex hormones. These precious and essential functional units can be altered by endocrine disruptors, which are numerically relevant environmental substances, which can potentially cause serious damage to the health, especially in particular crucial and sensitive phases of the human life.

9.2.1.2 Hormones

Hormones are chemical substances produced, in several types, by switching on several genes responsible for their synthesization; the word hormone was derived from “hormao,” a Greek term that means “put in motion” and later “that sets in motion”; they are active molecules, with chemical features of proteins derived also from steroids, equipped with high functionality and specificity. In order to perform their tasks, they are able to carry information and instructions from units of cells to another one, stimulating several cellular activities by specific receptors recognized. They act as “messengers” and are flowed out, by endocrine glands, directly into the glandular interstitial spaces (and not in ducts as occurs for the products of the exocrine glands) where they are then absorbed into the blood to be then distributed by the circulatory stream; hence, an adequate blood supply is then necessary to transport them to all the target body sites of these sophisticated molecules. After reaching the programmed destination, they bind to their target receptors, triggering a cascade of intracellular signals that induces that related cell’s actions. To ensure bodily functions, certain processes must be carried out correctly; therefore, hormones have to be produced in the right quantity; if an abnormal quantity of hormones is produced, common endocrine disorders develop as well as hormonal imbalance. Hormones are classified into five main categories and then subclassified into other much more specific groups: (1) by effects: metabolic (for instance insulin), kinetic (pineal), and morphogenetic (for instance thyroxine); (2) by chemical nature being water or lipid soluble: steroid, amine, peptide, protein, glycoprotein, and eicosanoid; (3) by the stimulation of endocrine glands: tropic or no tropic; (4) by the action mechanism: group I binds to intercellular receptors and group II binds to cell surface receptors, using then a second messenger; and (5) by the nature of function: local or general; furthermore, a direct classification sees the distinction in amine/peptide (that fit the cell membrane receptors) and steroid (that fit the intracellular receptors) hormones [12]. The sex steroids testosterone, dihydrotestosterone, and estradiol are linked, through the bloodstream, in an inactive form, to the sex hormone-binding globulin (hereafter SHBG), a globulin produced by the liver, probably involved even in metabolic disorders. To determine the effect of a hormone, its dose-response activity is necessary: therefore, for example, the concept of “non-monotonic dose-response curve” was also introduced and enhanced, defined as “a complex relationship between the dose of a substance and its effect, such that instead of a certain response simply increasing or decreasing with dose, the curve may be for example ‘U’ shaped” [13].

The main hormones, synthesized by the relative glands, are shown in Fig. 9.1 through a schematic illustration of the main organs, with some anatomical details, composing the endocrine system.

9.2.1.3 Receptors

Hormone receptors are specific sites that are already created in the fetal life, also known as “docking” molecules [10], placed on the surface membrane (hereafter MemRs) or inside the cell, like cytoplasmatic receptors (hereafter CRs) or nuclear receptors (hereafter NRs) as a sort of lock-and-key model (Fig. 9.3) [14]; for example, the estrogen receptors (hereafter ERs: ER_α and ER_β), that act as transcription factors, are intracellular proteins of the superfamily of NRs and are both CRs and NRs; NRs include also the androgen receptors (hereafter ARs), glucocorticoid receptors (hereafter GRs), progesterone receptors (hereafter PRs), and mineralocorticoid receptors (hereafter MRs) [12]. They can interact and bind “with and to” the endocrine hormones through different times and modalities: for example, protein-structured hormones react with the receptors located on the cell surface, and therefore the resulting events are more rapid; in contrast, fat-soluble products have the ability to diffuse through the cytoplasmatic membrane and the nuclear envelope, as steroids, estradiol, testosterone, progesterone, cortisone, aldosterone, thyroid hormones, and retinoids, and typically have interactions with receptor sites in the intracellular area, effectively causing protein synthesis which requires a relatively slower functioning. The link between the hormones and a specific receptor causes a distinct and precise physiological effect in the targeted cells. The bodily functions listed in the above section originate from the binding between hormones and receptors, which triggers a cascade of different events according to the type of hormone and the way of link; they need to be in adequate amounts in the target tissues and/or cells, which must be able to give the right reply to the hormonal signal; furthermore, if there is no correspondence among a receptor site and a hormone, no physiological reaction occurs. The connection between receptor functions and mechanism of action of environmental interferers has been extensively studied to obtain information as detailed as possible [14]; MemRs, CRs, and NRs can be stimulated, via several alterations, to increased, decreased, or reverse activities, based on the nature of the ambient substances and their biological potential.

An illustration of key characteristics of endocrine-disrupting chemicals include receptor ligand or agonist receptor antagonist, receptor expression, signal transduction, epigenetic alterations, hormone synthesis, hormone transport, hormone distribution or circulating hormone levels, and fate. — **Fig. 9.3**

9.2.2 Reproductive Health

Reproductive health (hereafter RH) had already been identified and addressed in its relationship with the likely adverse effects related to the environment [1, 8]. RH is a situation “in which the human reproductive activity is expressed in full physical, mental, and social well-being” [8] and occurs despite the presence of diseases also of the reproductive system [8, 15]; expressing a series issue for both health and environment, RH has become a thermometer of infertility-related disorders that can often be traced back to environmental etiology [8]. RH is constantly threatened by polluting and disrupting environmental factors such as consumer products, chemical substances, radiation, and stress [1, 7, 8, 14]. On the other hand, based on global assessments, socio-economic-cultural status, malnutrition, and infections must also be considered; it includes wide-ranging issues related to ambient and health [8].

Furthermore, adverse effects on human well-being and development of RH were reported, due to dibromochloropropane (hereafter DBCP), PCBs, methyl mercury, arsenic, and lead, having more data from studies on animals [8, 14]. The protection of RH starts from the purely technical concept that indicates the endocrine system as the organ responsible for controlling the reproductive system, its development, and its function; through the RH monitoring and its reproduction rate, the results in several areas with the identification of risk factors can be assessed and analyzed also to acquire new forecast and prevention strategies [8]. The factors capable of negatively influencing the reproductive health, in each of its phases, had and have gradually become the subject of important international studies and policies, aimed at epidemiological control and at development of preventive measures. Factors involved in negative RH interference, such as smoking, nutritional habits, infection disease, and stress, should also be mentioned for the sake of completeness; in fact, it has been widely reported in the literature how the use of smoking in pregnancy [8, 15] has been associated with an increase in maternal and fetal pathologies such as placenta previa, placental abruption and premature or low birth weight of the newborn at birth, and other serious obstetrical conditions due to “the numerous environmental toxins present in tobacco smoke” [15].

9.2.3 Environment

Ambient is a word derived from the Latin “ambiens,” interpreted as “everything to go around and to surround something”; it plays the predominant role in determining and regulating life cycles. In order to have a unique language and therefore frame the context examined below, the need to define the term environment thus emerges: it is the physical space, with physical and biological elements that interact, as well as the system of external situations, with biological features, surrounded and influenced by its conditions, where multiple forms of life are inserted [16]; it can be natural or artificial, and marine or mountain, and must be under sets of measures, regulations, and laws to protect it from any kind of pollution or alteration; the ambient issue, as it concerns health, has become central in every state and nation, globally. In terms of etiological agent, the same definition of environment, provided by the WHO, denotes the importance of the issue: “environment is a major determinant of health, estimated to account for almost 20% of all deaths in the WHO European Region”; in 2010, the focus was also on the need to open a new action era, based on the past world indications, for our health and environment [17]. The Italian Constitution protects the ambient through the fundamental principles and states: “The Republic promotes the development of culture and scientific-technical research; it protects the landscape and the artistic heritage of the nation. It protects the environment, biodiversity and ecosystems also in the interest of future generations. State law governs the methods and forms of animal protection” [18]. The known dependence between living beings and nature has therefore increased worldwide awareness of the negative effects of the ambient on the health; stratospheric depletion of ozone, long-range air pollution, climate change, toxic waste export, acid deposition, and loss of biological diversity are some of the global issues. It has been known for decades that the endocrine system and the reproductive functions, regulated by the first one, are greatly influenced by unfavorable environmental factors. Moreover, in the world, there are negative socio-economic conditions and cultural and/or pollution influences that compromise the reproductive health, which are constantly increasing; multiple chemicals are present at the same time and overlap with other ambient problems, making it difficult to assess the effect of a single harmful element. Epidemiological studies and data collected, under precise and systematic surveillance, are basic sources for the acquisition of new and updated information and are areas of fundamental importance for weighing the gravity and the risk of harmful factors and for developing approaches and prevention strategies. The determination of the concept environment, in ecology, includes two closely related aspects: the physical and biological contexts (for example: humidity, climate) that surround an organism, a human population, or a biotic community; from the biological point of view, it means what influences life and development; therefore, the entire biosphere is a set of several environments on the Earth, expressing varying levels of global environmental contamination by several xenobiotic compounds, also used for metabolic functions of microorganisms capable of catabolizing them by processes such as degradation and enzyme or gene pathways. Understanding of the real environmental conditions of a given population can lead to the study of useful performances for the protection of the public health, and therefore also in the field of reproductive health. Many environmental factors have the capacity to influence the latter aspect of a particular community: for example: ethnic, health, chemicals, radiations, infections, malnutrition, stress, social status, and cultural influences. Absurdity situation as in some countries and major technological and economic developments have shown a negative impact on the population, while, in countries developing with many life difficulties, the lack of accessibility to reproductive health care is the main issue of people. Furthermore, several scientific evidences have demonstrated that the negative effects of various environmental components, as in consumer products, water, and food, as smoke, polycyclic aromatic hydrocarbons, air pollution, pesticides, and others, are much more incisive on minority populations, fetus in utero, children, and adolescents. Thus, it gave rise to the need to carry out also targeted studies on individual exposure to the environmental chemicals, as well as on the ecological action as an etiological factor.

9.2.4 Endocrine Disruptor Chemicals

Following the above introductive overview, it can be understood that a malfunction caused by human diseases of some endocrine unit components may, less or more severely, influence a lot of matters regarding human physiological homeostasis and/or functions. Indeed, in mammals, endocrine messages, coordinated by MemRs, CRs, and NRs [14], are responsible for RH, placenta-embryo-fetal growth, energy management, electrolyte balance, and other fundamental bodily functions and systems [19].

Several evidences had demonstrated that various ambient negative conditions are able to falsify human endogenous hormone activities, compromising their regular tasks; many natural (for instance, phytoestrogens in soya) or synthetic hormones and other man-made chemical molecules (for instance, pesticides or air pollutions or plastic substances for industry) may mimic, interact, or interfere with the physiological hormonal functions [1, 3, 8, 14, 20]. Various hypotheses had been formulated of dangerous disturbance capacity for almost 2000 substances, concerning, at least, one of the three main hormonal pathways, that is, estrogens, androgens, and thyroid [3]. The U.S. Environmental Protection Agency (hereafter EPA), studying both ecological and human health effects and working on recommendations for future research, had given those molecules, which have a disturbing action on the endocrine system, a definition as “an exogenous substance that interferes with synthesis, secretion, transportation, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body responsible for homeostasis, reproduction, and development” [21]. Moreover, there was the WHO 2002 EDC formulation as “an exogenous substance or mixture that alters functions of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations” [20]. Therefore, data collection studies had begun, also according to the guidelines developed to date by the EPA, first on the consequences of the aforementioned molecules on human and animal health, rather than the mechanisms of action and the involved organs [21]. Those dangerous materials were also identified as heterogeneous and deriving from various sources present in the ambient; therefore, the WHO and the United Nations Environment Programme (hereafter UNEP) had elaborated another indicative and explanatory term for those compounds, “Endocrine Disrupting Chemicals” (hereafter EDCs), that are artificial molecules (exogenous/xenobiotics substances) with a heavy negative impact on health, being able to interrupt, as well as selectively modify, the hormonal axes regulating the reproductive systems and those responsible for body growth; moreover, the same WHO/UNEP Programme had identified “800 environmental chemicals that are known or suspected to be capable of interfering with hormone receptors, hormone synthesis, or hormone conversion” [22, 23]. A similar definition for EDCs has been elaborated by the Endocrine Society: “an exogenous (not natural) chemical that interferes with any aspect of hormone action” [24]. EDCs, due to their adverse aftermath, are in continuous analysis and monitoring by the WHO, the European Commission (hereafter EC), the UNEP, the United States Food and Drug Administration, the National Institute of Environmental Health Sciences (hereafter NIEHS), the EPA, the Endocrine Society, the International Federation of Gynecology and Obstetrics (hereafter FIGO), the Chemical Agency, the European Food Safety Authority (hereafter EFSA), the European Commission’s Joint Research Center, the Centers for Disease Control and Prevention (hereafter CDC), the American Academy of Pediatrics, the Organisation for Economic Co-operation and Development (hereafter OECD), and international societies and groups as EDC experts, active in updates and debates on the evaluation of risks, epidemiology, and prevention of the negative exposure effects on the public heath [25]. In fact, through the WHO/UNEP 2012 document, the UNEP and the WHO updated the 2002 International Chemical Safety report, which highlighted the significant increase in endocrine abnormalities and disease in humans, likely due to EDC exposure [23].

Moreover, critical “windows” of greater sensitivity in human life, as puberty or embryo-fetal growth, were identified as highly at risk for the development of irreversible effects after exposure to EDCs, which act with a mechanism of action both at the tissue and cellular levels. The WHO and the EC have screened more than 100 molecules as potential EDCs, in order to perform strategies for the sustainability of an ambient of better quality [22, 25, 26]. Furthermore, following a precise rationale and starting from the model of carcinogens, ten EDC key characteristics have also been developed (Fig. 9.3), based on their effects and hormonal action; to perform this evaluation, models such as (1) diethylstilbestrol, (2) bisphenol A, and (3) perchlorate were used. In fact, this interesting, schematic, and effective approach to this global issue offers a uniform evaluation of the key characteristics to identify the EDCs with research methods aimed mainly at their ability to negatively interact with the endocrine systems [14]. The three models used can be summarized as follows: (1) already abovementioned drug used to avoid miscarriage or preterm labor with controversial results; (2) a drug used in the first half of the 1900s and currently found, for example, in plastics also for medical and sports artifacts, in materials to transport food, or in dental issues and paints; (3) those found in water, vegetation, and soil and associated with rocket propellants, pyrotechnic article explosives, and missile motors [14]. The EDC was even described as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process” [22]. Compared to the initial studies, from which it seemed that they could only act on and through the nuclear hormone receptors (for example receptors of estrogen, androgen, progesterone, thyroid), recent evidence shows that their function is also directed on membrane hormone receptors, steroid and nonsteroid, and orphan receptors (with no ligand identified) [13, 27]. Besides, environmental factors were evaluated (also by numerous epidemiological and observational studies on animal models and few on human cohorts) during pregnancy for maternal-fetal and/or neonatal well-being without observing the preconception period: therefore, it was also recognized as a further sensitive window for both sexes. Epidemiological studies have found associations between EDCs and adverse outcomes on RH, pregnancy, male/female fertility, and early life; furthermore, biological samples were collected in a study of male and female cohorts in preconception, pregnancy, and various trimester times [28]. The access routes of the dangerous substances can be several: humans, during everyday life or work activity, come into contact with EDCs through food and beverages, pesticides, and household and cosmetic products; concretely, the contact may be through diet, air, skin, and water. The physiological endocrine functions are sensitive to even small changes caused by low hormone levels, determining the related significant biological effects; therefore, scientists and expert analysts have realized that even low doses of EDCs may be dangerous.

9.2.4.1 Endocrine Disruptor Chemicals and Action Overview

The negative consequences of EDCs in wildlife had already been reported since the 1950s [3]; since then, hundreds of thousand dangerous materials to the health of living beings, humans in particular, have been identified; epidemiological and biomonitoring studies were then carried out to control EDCs which, as already indicated, could interfere with hormonal functions. At first, there were evidenced issues regarding the amount of the sperm and cancers as prostate, testicular, or breast, which could have an endocrine correlation and ambient etiologies [5, 21]. Subsequently, over some decades and thanks to the acquisition of new scientific elements, researchers have refined the key characteristics such as receptor agonist/antagonist or modifiers of the receptor expression, or directly the target tissues; particular mention must be made of the three main human endocrine axes, EDCs’ potential targets: hypothalamus-pituitary, adrenal, and thyroid glands [23, 27, 29, 30]. Moreover, in 2013, the EC indicated three EDC action criteria as fundamental for their recognition: “(1) endocrine activity, (2) deleterious and/or pathologic endocrine-mediated activity, and (3) cause–effect relationship between substances and endocrine activity in exposed subjects” [31, 32]; the Endocrine Society also mentioned more EDC action mechanisms such as “interference with any aspect of hormone action” [24], DNA methylation, DNA acetylation, and histone alterations, defined as “epigenetic changes” [24, 32]; they can act like genomic to exert some biological effects practically [12]. Furthermore, a greater susceptibility and sensitivity to toxic molecules of the subjects were also highlighted monitored by various research studies in the ambient epidemiology area, based on the human age, such as fetal life and childhood [33, 34]. Those molecules are mostly from the sectors of industrial productivity, aimed at forming materials for various activities and jobs; their access routes are mainly through solid and/or liquid feeding, breathing, and contact; along with the most popular lists, the main distinction is based on the criteria of persistence, as DDT, or non-persistence, as phthalates (hereafter PhTh) [33,34,35,36,37]. On the other hand, for other opinions, there seems to be no international effective schedule of EDCs, not even based on the action mechanism [14]; a basic list is given below, in order to better outline the known data, obtained from studies on human and experimental models that concern global environmental contaminants.

Persistent Organic Pollutants: Persistent organic pollutants (hereafter POPs), coming from air pollution, are carbon-based organic chemicals, also classified as a group of EDCs man-made for industrial utilization, then released into the ambient, characterized by stability and a long half-life, and therefore classified as “persistent”; they get the ability to be bioaccumulated in living organisms and also humans. Some POPs, even of high molecular weight, can also cross the human placenta and get to the fetus, consequently [38]. The POPs’ effects on human/animal health involve multiple organ systems such as nervous, reproductive, and endocrine up to carcinogenic effects; their toxic potential on health is associated with several variables, such as the synergy with other substances, the capacity to be absorbed and accumulated, as well as the ability to interact with MRs, CRs, and NRs present on the target tissue of hormone products.
- Dichlorodiphenyltrichloroethane (DDT, DDTs, p,p’-o,p’-DDT, p,p’DDE): This POP is an insecticide used in agriculture, banned in the United States since 1972 [39] and still in use in some countries, especially for the malaria control; DDT was paid attention due to its effects on the reproductive and sexual systems [2, 14, 25]; DDTs and its metabolites, as diphenyl dichloroethane (hereafter DDE), often present together, have different chemical structures and different capacity of estrogenic/antiandrogenic actions as EDCs [14, 40] and possess a long persistence in animal tissues and environment; therefore, it can be taken by humans in every vital epoch through food or by contact with contaminated products, which then accumulates in the adipose tissues and crosses the placental barrier in pregnant women (see also in dedicated section). There were many papers, also contradictory ones, that found obesogenic and ovarian DDT consequences, based on animals’ experimental evidences. In order to highlight the concept of perinatal exposure, it was examined in the Child Health and Development Studies (hereafter CHDS) cohort, starting from the serum samples collected from the first generation of patients, the grandmother ones, in the 1960s; this was the first human research to hypothesize the association of grandmothers’ exposure to o,p’DDT with the outcomes in daughters and granddaughters (subjects belonging to three generations) regarding early menarche time, adiposity, and obesity that are mostly risk factors for breast cancer [40].
- Per- and Poly-fluoroalkyl Substances (PFASs/PFCs/PFOA/PFBA/PFHxA/PFHpA): PFASs are man-made fluorinated polymer/non-polymer compounds; due to their chemical-physical characteristics (repellency, lipophilicity, thermal-chemical stability, hydrophobicity, and resistance and also the natural process of biotic degradation, photolysis, or hydrolysis), they are widely used in industrial sectors, such as tools for personal care, firefighting foams, nonstick pan, paper, textiles, coatings, and food storage. PFASs are released into the environment, are persistent and nonbiodegradable, continue to bioaccumulate without decomposing, and could contaminate water and foods, also by their packaging; new evidences indicate that PFASs are dispersed through the air over long distances: widespread exposure to PFASs has been detected in the US population. The human body comes into contact through food, ingestion, or inhalation of dust. PFASs could hold antiandrogenic potential and a link with male effects due to the interaction with androgen receptor activity and sex hormones; moreover, they can reach the fetus through the passage of the placental barrier [41, 42].
- Polybrominated Diphenyl Ethers (PBDEs): PBDEs are organohalogen substances used to make flame retardants for household products such as furniture foam and carpets. They can get bromine, fluorine, or chlorine atoms and from these characteristics derive the various names assigned to the different chemical compounds. PBDEs are lipophilic with androgenic and estrogenic abilities, thus being able to interfere with the development of the sexual sphere by postponing the male pubarche or anticipating the female menarche [43]; further data will be needed to support the evidence ascertained so far, also related to the body mass index (hereafter BMI) of the monitored subjects in some studies [43].
- Polychlorinated Biphenyls (PCBs): PCBs are man-made compounds used to make electrical materials like transformers and are also used in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers; they are persistent and therefore difficult to dispose of; even though they have been banned in the United States since 1979, the exposure still occurs today, due to the presence of previous artifacts or mixtures and even 15 years of estimated half-life; several monitoring and epidemiology studies on humans and experiments on animals have reported the effects of PCBs on newborns’ weight and on head circumference, due to prenatal exposure, through their passage from the placental barrier [44]. Moreover, PCBs have androgenic, estrogenic, and antiestrogenic effects [45,46,47], and, with their subtype, they turn on a thyroid receptor [14].
Bisphenol A (BPA): BPA was first synthesized in 1891 and is used to make plastics and epoxy resins and found in many products (for instance, food storage containers); humans can be exposed through food mostly; it was never used as a drug. Of all EDCs, BPA is probably the substance endowed with greater estrogen-like capacity; many epidemiological research studies reported about the sexual maturation of girls exposed to this substance in utero, but the findings were controversial [43]. This theme is most in focus by experts in the sector, even if further investigations are needed to identify all the molecular routes involved in their capacity to act as endocrine disruptors [14, 43].
Dioxins (2,3,7,8-tetrachlorodibenzo-p-dioxin, hereafter TCDD): These are industrial substances achieved as a byproduct in herbicide manufacturing and paper bleaching; their presence in the ambient is due to waste burning and wildfire; dioxin exposure appears to be associated with female cancers, impaired fertility/fecundity, endometriosis, and incorrect time of puberty age [19, 24, 42].
Perchlorate: It is a substance produced by the pharmaceutical, aerospace, fireworks, and weapon industries. It can be found in drinking water. Its structure is in some respect similar to the iodide ion; therefore, it can interfere with the physiological function of the thyroid, causing, as an inhibitor, the blocking of the synthesis of thyroid hormones with its negative effects on body metabolism [48].
Phthalates (PhThs: dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), benzyl butyl phthalate (BzBP), polyethylene terephthalate (PET), and others): These are diesters of phthalic acid with the characteristic of non-persistence; for example, polyvinyl chloride (PVC) is used to make plastics more flexible; they are also used in some food packaging, detergents, cosmetics, children’s toys, and medical devices; they can come into contact with humans by food, water, skin, or breath. These EDCs may interfere with the physiological function of the hormonal axes that regulates the development of the male and female sex; several studies have evaluated phthalate metabolites in urine to obtain data without risk of external contamination [49]. Alterations in the masculinization of the male fetus were reported: experts showed, on a small cohort, a decreased anogenital distance in human male infants, exposed to phthalates, during their intrauterine life [49]. Furthermore, phthalates’ association with earlier puberty in females and the hypothesis of an estrogenic role by PET of water packaging were highlighted [50]. However, other studies show different evidences; therefore, phthalates could exercise antiandrogenic and estrogenic skills, but more data is needed to confirm the aspects related to pubertal timing [43].
Phytoestrogens: For decades, they have been included in the diet to meet nutritional needs, and also as a substitute for animal proteins, found in many food plants, like soya; they have hormone-like activity; and their presence has already been correlated to the increase in SHBG synthesis, probably interfering with the action of endogenous estrogens [5]. However, to date, other phytoestrogens, such as genistein and daidzein, are in soy products, like tofu or soy milk, and their biological effects are probably attributable not only to their environmental presence [5].
Parabens: Parabens are chemical preservative substances, 4-hydroxybenzoic esters in fact, used, for over 50 years, in detergents, food, pharmaceutical, and cosmetics to fight fungi and several harmful matters; in vivo and in vitro evidences show that, among other types, butylparaben and propylparaben can negatively interfere with the endocrine system also due to their possible estrogen-like action [51]. In addition, parabens’ presence in the adipose tissues of breast was observed, made possible by their characteristic of mild hydrophobicity; however, to examine the connection with the breast cancer etiology, future observation of parabens’ and other EDCs’ exposure effects is needed [51].
Triclosan (TCS; 5-chlorophenol): TCS, first used as a pesticide since 1969, is an antibacterial and antifungal chlorophenol and may be found in some antiseptic, disinfectant, and personal care products, like toothpaste, soaps, shampoo, body lotions, and creams; antibacterial products with triclosan were excluded by the FDA from sale in 2016–2017; it was included to EDC list [23]. People may be exposed to this endocrine disruptor through the antiseptic and cosmetics used, via skin and/or ingestion; it was first detected in human milk and then in plasma and urine [52]. In essence, TCS could get the ability to interfere with the endocrine functions and RH, related to its chemical structure (2-phenol); its action as estrogenic molecules has been highlighted, even if the available little epidemiological data are contradictory [52].
Metals: Metals are substances with high electrical and thermal conductivity, and also high ductility and malleability among other properties; heavy metals are difficult to metabolize; therefore, aquatic environment/organisms can accumulate them; in fact, these metals are considered the main pollutants of aquatic reserves. There are experimental and epidemiological studies on both animals and humans, which have reported negative effects on organisms. Moreover, some of them can cross the placental barrier, reach the fetus having a teratogenic effect, and disrupt the hormones needed for the pregnancy, with the following increased risk for stillbirths or spontaneous abortion [12, 35]. According to the EDCs’ definition [20,21,22,23,24], this group of contaminants have been included in the category of endocrine disruptors, and several analyses have been oriented on their unsafe action mechanism. Some heavy metals (copper, aluminum, cadmium, and lead, for example) have been identified as “metalloestrogens” for their interference, also as agonist, with the physiological function of estrogens, ERs, and the consequent elements of response to that hormone.
- Cadmium: Cadmium (hereafter Cd) is a contaminant that can be found in significant quantities in ground and water collection basins due to its release from various polluting industries [12]; humans can come into contact with Cd through the intake of contaminated food or contact with relative adverse consequences on organs and body systems, as widely reported in literature also for the production of GH, ACTH, and TSH hormones in rats (even ovary progesterone) and human plasma [12]. Furthermore, experimental study had evidenced a decrease of placental progesterone production from human trophoblast cell cultures, by interfering in the cholesterol accumulation, necessary for this essential process; on the other hand, these data were contradictory according to other in vitro and in vivo studies [12]. On the other hand, prenatal exposure to Cd had been correlated to negative pregnancy outcome resulting from placental defects, and female early puberty time in the offsprings [12]. Due to Cd body storage organs, researchers also highlighted that Cd exposure can contribute to diabetes mellitus (hereafter DM) development and progression [53].
- Mercury: Mercury (hereafter Hg) is widely present in several natural environments, industrial artifacts, and food chain; frequently, Hg exposure occurs through the intake of contaminated food, especially fish. Hg exposure appeared to be related to the increase in female hormones, by testing, for instance, Hg levels in human blood and hair, therefore hypothesizing its role in the stimulation of this precise hormonal synthesis [12]. There were also evidences that correlated Hg levels with the thyroid endocrine system [12]. Methyl mercury, the natural/synthetic bioaccumulation form (hereafter MeHg), had already begun to be considered in relation to neurological alterations in exposed fetus and children [1]; in 2004, the FDA and the EPA set up a declaration to warn the population about the adverse effects of MeHg on brain development.
- Arsenic: Arsenic (hereafter As), like other heavy metals, is present in several sectors of industry and agriculture; human exposure occurs both for work activity and for contaminated food intake. Many experimental studies have shown that the As’ dangerous consequences for human health are due to its role as EDCs, interfering with some types of hormone receptors and their expression [12, 53]_. Moreover, due to As body storage organs, such as Cd, was also highlighted as As exposure can contribute to DM development and progression [53].
- Lead: The role of lead (hereafter Pb) exposure in pregnancy should be mentioned; several scientific evidences have hypothesized the correlation between lead and preeclampsia (a serious pregnancy disease characterized by hypertension and proteinuria); moreover, a meta-analysis showed a high association between the bodily presence of this metal and the development of gestational hypertension through the possible increase of vasoconstrictive substances and reduction of vasodilating ones, with the related vasoconstriction and placental ischemia, and also proteinuria due to a direct adverse action on the renal and endothelial physiology. In particular, the lead levels and their dose effect were also detected.
Tobacco Smoke: The use of tobacco smoke is a matter of great impact: it is evaluated that for 2030, the deaths caused by its use will be more than 8 million [15]. Over any period of human life, tobacco smoke is a notoriously harmful habit for every aspect related to human health. Moreover, it had already been reported that the use of tobacco smoke, or its passive exposition, in the gestational period negatively affects the fetal development and is associated with respiratory disorders and defects of brain development, intrauterine growth, and respiratory disorders in the fetus and newborn [8, 15]. Cigarette smoke has more than 4000 chemical compounds, and many of them have the ability to interfere with brain processes; in particular, nicotine holds the detrimental, serious “neuro-teratogen power” by interfering with neuroanatomy, cell life, and subtypes of neuronal nicotinic acetylcholine receptors (hereafter AChRs), which are found in the fetus as early as the first trimester of pregnancy [15]. Besides, cigarette use is an important source of Cd, with the consequences, among others, mentioned in the dedicated section [53, 54]. Also, there is severe constellation of obstetric and neonatal complications such as premature delivery, placental disorders, and sudden infant death syndrome (hereafter SIDS) [15].
Microplastics (hereafter MPs): MPs, which term had been coined by a marine biologist professor in 2004, are polymer chains made up of carbon and hydrogen atoms, are not biodegradable, are very small snippets of plastic, and measure less than 5 mm (0.2 in.) in length, according to the definition of the world’s leading experts (United Nations Expert Panel: United Nations Environmental Programme, UNEP) [55]. MPs result from man-made matters or from the environmental degradation of various plastic products; chemical additives are also present in MPs, as phthalates, PBDE, and tetrabromobisphenol A (hereafter TBBPA). In recent years, the public opinion has led to greater scientific investigations to increasingly promote strategic operational interventions for monitoring and prevention. Through a prospective preclinical observational study, based on a plastic-free protocol, MP particles have also been identified, for the first time, in the human placenta (Fig. 9.4), and precisely both in the maternal-fetal sides and in the amniochorial membranes [56]. In this context, MPs seem to be realistically transported in the blood system by maternal respiratory or gastrointestinal organs, where they could also become carriers for environmental pollutants and additives which are elements with adverse effects, thus becoming EDCs with probable consequences first on embryo/fetal growth and maternal well-being and afterwards in the long-term life periods. Given the well-known fundamental role of the placenta as an interface between maternal environment and fetus, the above evidences would underline the need to investigate the entry routes and the consequences of MPs [56].

A graph plots intensity versus Raman shift. The graph line fluctuates with high peaks between 1250 and 1500 per centimeter and at 5000 intensity. It has an inset squared box with stained M P particles above with the label hash 11. The same box is represented below. — **Fig. 9.4**

9.2.4.2 Endocrine Disruptor Chemical Effects on Human Body Systems, Reproductive Health, Prenatal Exposure, and Offsprings

To the Barker “fetal origins” hypothesis, which highlighted, in models in utero, deficiencies nutrition and metabolic syndrome/cardiovascular malfunctions, and which had been focused on the analysis of the development of the state of health and disease, the prospective role of environmental impact, by its chemicals elements, was also included, especially in the most sensitive “windows” life of the human growth, already from the oocyte stage that is “in egg exposure” [14, 22, 40, 46, 57,58,59]. From this hypothesis, “a new vision of an optimal early human development” is highlighted as a starting point for likely short- and long-term effects on the well-being of the infant and child, considering both birth weight and body load during infancy and beyond [57]. Importantly to emphasize that, during pregnancy and early life, the developmental phases of the fetal organs and systems, which then continue into the postnatal time, make, among the others, the second trimester of gestation particularly vulnerable to negative interference from external stimulation [3, 46]. Particularly, in womb, EDC exposure may interfere with the life of the fetus and the following generations, as well [25]. Afterwards, later in life, ambient substance interference could alter the physiological development of gonadal cells, resulting in fertility/implantation reduction, fetal chromosomal disorders, and dysregulation of fetal growth with consequences like small for gestational age (hereafter SGA) or intrauterine growth retardation (hereafter IUGR) and similar [8]. Epidemiological human studies, both in men and women, which is the fundamental discipline for public health/disease analysis [8], highlighted the correlation between environmental chemicals, even enhanced by nutritional factors, and adverse RH effects, on male and female fertility and on pregnancy outcomes and increased risk of childhood and adult diseases; moreover, clinical studies projected to assess the impact of the ambient and lifestyle components on fertility and pregnancy outcomes were therefore created. An extremely important concept has been focused on the issue that the “susceptibility to the potential health impacts of toxic environmental chemicals can increase when exposure occurs during critical and sensitive developmental periods, such as during pregnancy, childhood, and adolescence” [22]. Therefore, it can understand the link with the Developmental Origins of Health and Disease (hereafter DOHaD) theory related to the lifestyle of each lifetime (Fig. 9.5) with both epigenetic and endocrine interferences. Hence, the identification of the critical and sensitive “windows” of the individual’s life was possible, which represent the points of greatest danger during the presence of potential EDCs [22, 59]. The extent of endocrine interference caused by EDCs is also influenced by the age of the exposed subjects, types of molecules, their capacity for negative action as agonists or as antagonists, and dose-response dynamics [3]. Moreover, in the body context, the placenta, which is a transitory organ essential for reproduction, is studied in particular for its vulnerability given by the presence of hormone receptors for steroids on its tissues [46]; the EDC exposure of this functional unit is being evaluated, thanks to studies that will, in any case, need to be standardized, even taking into account the product of conception sex [46].

A diagram represents E D Cs exposure. It represents the growth phase from prenatal, childhood, puberty, and adulthood. The growth phase undergoes epigenetic changes and interferes with hormone biosynthesis or metabolism. The exposure leads to metabolic disorders, male and female reproductive abnormalities, and cancer. — **Fig. 9.5**

The complex and fascinating process of placental development (Fig. 9.6) could be compromised at various times by many EDC molecules and their congeners, thus interfering with the multiple placental functions [60]. At present, the data revealing the adverse effects of EDCs derive from research studies on animals, mainly; evidence of plausible links between EDCs and multiple human pathological pictures includes adverse outcome on metabolism and RH and increase in risk factors for cancer [36]; it is evident that diseases affecting various organs or systems can directly or indirectly extend to the RH, which is physiologically subject to changes in other body compartments. In addition, exposures to low levels of toxic substances must also be considered, especially in vulnerable life periods, with the probable transgenerational and/or epigenetic injurious impacts; these are some of the criteria that differentiate EDCs from other toxic substances, including the body response to non-monotonic doses [36].

An illustration on the development of the fetus and placenta from fertilization to full term. It shows lower oxygen from week 0 to 13 and higher oxygen from week 13 to 40. It marks uterine vessels, uterine wall, cytotrophoblast, syncytiotrophoblast, placental villi, and maternal blood. — **Fig. 9.6**

9.2.4.3 EDCs’ Effects on Female and Male Reproductive Health

RH should depend on “cultural, ethnic, social, political, economic, and health factors and strategies to ensure that RH protects the community from the environment and develops a positive interaction between humans and their environment, taking into consideration that the environment affects the persons, and the person affects the environment” [8]. EDCs’ adverse effects on the global human reproductive systems were already reported in relation to, for instance, Bhopal and Chernobyl events [8], as well as to the DDT [2, 25] and DES [14, 25] interference, also due to prenatal exposure; through only partially known mechanism of action, these harmful compounds can interfere with RH [36]. Moreover, it had already been reported that the prenatal/antenatal exposure events to chemical environmental substance could have serious adverse effects on RH, because of malfunction of the relative interconnected systems [8]. Like any other aspect related to bodily health, RH shows its first signs of development and differentiation in the intrauterine life and then continues in well-coded postnatal stages; during each week of gestation, pathological processes of various types can be established that have a decisive influence on the life of the individual, both in terms of endocrine pathologies and in terms of impaired reproductive functions due to RH alterations. Furthermore, few epidemiologic data point out how environmental chemicals, more than lifestyle and nutrition, should be, at the same time, factors evaluated as a whole on the RH impact during the preconception period for both women and men [8, 59]. Through an ongoing monitoring, during male and female preconception time and pregnancy time, a prospective study showed, for example, higher urinary concentrations of phthalate metabolites in association with low egg production, a decreased odds of embryo implantation, and an increased risk of pregnancy loss in patients treated for infertility (drug-induced pregnancy) [28]. Moreover, in a dose-dependent way, a decrease of semen quality and higher monobutyl phthalate levels were found to be correlated; more than 40 biomarkers of environmental chemical exposure were tested for a broad overview of the association between substances, dietary elements, and negative effects [28].

1.
Female. In the etiopathogenesis of female pathologies, the responsibility of adverse environmental factors, as xenoestrogens, or other EDCs must be carefully considered; those chemical substances exercise their function by mimicking the endogenous estrogens. The presence of pesticides, as PCBs, dioxins, DDT, and others, in fat tissue and breast milk, had already been reported [3]. Factors related to poor access to medical and health care, stress, and socio-economic status could potentiate the effects of the chemical exposures on female/maternal safety. In general, many alterations of the female reproductive mechanisms have been observed, probably also due to EDC exposure [19]; the main disfunctions are in the following two classes: (1) short-term issues, i.e., pregnancy outcome with SGA/IUGR, embryo implantation, and fertility rate, and (2) long-term issues, i.e., puberty timing, fibroids, polycystic ovary syndrome, endometriosis, and cancer; the latter three alterations are more frequently associated with EDCs [24, 42].

The puberty, precocious-central or early, and menarche age have been studied in relation to the effects of endocrine disruptors that could interfere with hypothalamic function by epigenetic alterations. Animal model studies have found epigenetic transgenerational impacts from DDT and DDE exposure, resulting in polycystic ovary syndrome and primary ovarian insufficiency with granulosa cell alterations [40]. Also in the first human cohort study, the effects of POPs were analyzed on three generations: maternal, in utero, and in egg exposure, with the evidence of early menarche in egg exposure generation; obesity and premature menarche, known as risk factors for breast cancer, could alter the regular development of the studied generations [40]. On the other hand, EDCs’ role is still debated; however, other evidences have showed earlier breast development and earlier menarche time in female offspring, exposed in utero to DDT/DDE [43]; furthermore, a reduced fertility and a higher risk of breast and female genital tract cancers, in females exposed in utero to DES, during their embryo-fetal stages of life, had been widely reported, as also already mentioned in the introductory section [5, 42]. Likely, the main implicated compounds are bisphenol A, phytoestrogen, and dioxin [19, 24, 42].
2.
Male. It has been shown that during in utero life, the differentiation of the male genital tract occurs, through the Müllerian duct involution and the testes’ descent into the scrotal apparatus; hormonal management was found to be essential for these processes [5]. Over the decades, alterations in the physiological functioning of the male reproductive tract have been reported, but the role of exposure to EDCs has been debated [20]. It had already been suggested that sperm amount and quality could be compromised by milieu pollution [8]; furthermore, some glycol ethers and Pb may begin to be related to malfunction of male fertility [8]. Moreover, the concept of interference on Sertoli cells by estrogens, and related consequences on the fetal pituitary circuit in FSH production and later in sperm amount, was introduced [5]. Later, the acquired knowledge identified more alterations, such as the decrease in sperm count and motility, that could be attributed to the presence of pollutants with estrogen-like activity in the fetal life of affected patients; “phthalate syndrome” in animals was also reported, related to the testicular dysgenesis in humans exposed prenatally, probably due to those antiandrogen EDCs’ impact on programming and development of fetal gonads [49]. Furthermore, there were results indicating male sex-dependent pharmacodynamics and clearance of PFAS with much higher exposure; through the passage of the placental barrier, the male fetus could suffer from their antiandrogenic potential [41]. The main male effects are in the following issues: anomalies of the pubertal period, poor semen quality, cryptorchidism (undescended testis), hypospadias, low serum testosterone level, and testicular cancer [36].
3.
Maternal Health, Placenta, and Pregnancy Outcomes. As already highlighted in the previous sections, the EDCs’ exposure can be detrimental and dangerous, associated with the development of pathologies affecting both the maternal and the fetal compartments, during the gestational (Fig. 9.6) and postnatal “critical” and “sensitive” periods (Figs. 9.5 and 9.6) [22, 24, 57, 59,60,61].

Generally, long-term consequences on the reproductive systems, from prenatal and perinatal exposure to toxic agents, have already been suspected and identified [8, 24]. Hence, starting to delineate the dimension of “Pregnant Utero Biosphere” (hereafter PUB, Fig. 9.7), the pregnancy time must be particularly attentive as the developing fetus and placenta could undergo alterations and consequent long-term diseases [22, 24, 59, 62]; it is a well-established notion that fetus is extremely more susceptible to external agents also due to the immaturity of both its detoxification mechanism and its immune system [38]. Moreover, many papers concerning pregnancy and lactation have already identified the effects on both the maternal and fetal organism and their offspring, introducing the concept of transgenerational inheritance, where an alteration, EDC induced, can manifest itself in the future generations [30, 34]. Among a lot, there were evidences of neurotoxicity evaluated on animals’ and humans’ prenatal exposures to MeHg, Pb, and pesticides [58, 59]; MeHg had even been found at higher levels in the fetal cord blood than in the mother [59, 63]. The placental development, with the relative co-mixture of the maternal-fetal sides, known as “placentation,” is undertaken by the embryo which literally attaches itself to the uterine wall with the invasion of its trophoblastic cells; they gradually enter deeper and deeper uterine body in a stage called invasion [64]. Any events/substances with adverse effects/disruption on placental development phases and function, with their natural repercussions on the pregnancy outcome, must be scientifically and inevitably a basic concept for the protection of RH, which must be known and managed globally; several “environmental sphere” and PUB (Fig. 9.7) components can be adverse factors and targets with varying severe degrees of prenatal impacts such as risk of miscarriage, stillbirth, premature delivery, placental alterations, SGA, IUGR, low birth weight, and congenital anomalies and/or SIDS [35]. Furthermore, it is also necessary to mention again one of the nicotine effects, which are possible due to its action on the AChRs; it has been shown that maternal tobacco smoking, and some of its components, during pregnancy, has detrimental effects on the placental physiological functions and on the fetus because of their capacity to cross the placental barrier and to modify the brain cell proliferation and differentiation by the AChRs; the increased risk of cognitive and/or auditory alterations would therefore derive from the cell loss and neuronal deficiencies [15, 65].

A concept illustration called the Pregnant uterus biosphere depicts the protection of the fetus and pregnant uterus through total environmental defense and security. It represents a handmade pencil drawing and a digital processing of it. — **Fig 9.7**

Also exposure to inhalational anesthetic exposure or to low levels of Pb could be associated with an increased risk of infertility and miscarriage, respectively; moreover, exposure to radiation, pollutants, pesticides, and organic solvent can be associated with the obstetrical complications listed above; in addition, forms of stress, even physical and occupational, can influence gestational outcome even up to an increase in the incidence of preeclampsia probably linked to excessive release of catecholamines [11]. Even if the PFAS interference on hCG (Fig. 9.5) levels is documented, further studies will be needed to evaluate the negative effects of any PFAS exposures on female well-being and gestation [42]. Moreover, a PFOA inhibitory capacity on the rodent placenta and, consequently on pregnancy has even been identified [42].

From epidemiological evidences in also in vivo and ex vivo models, the placental presence of PCBs had been related to the decrease in the placental size [45, 46]; precisely, an alteration of syncytiotrophoblast volume and of placental growth factor (hereafter PIGF), with a compromised remodeling of the spiral artery and a likely placental disruption, has been documented in a little cohort of normal pregnancies [45]; already in the past, the impact of PCBs’ prenatal exposure on newborns’ weight and head circumference, due to their placental transition, was documented in pregnancy outcome of women who had taken contaminated lake fish [44]; however, since PCBs are present in a mixture, any specific placenta effects of the various components are complicated to select [45, 46]. The role of exposure to EDCs in relation to premature delivery must also be considered, in particular, the presence of PhTh metabolites [66].

In the general framework increased by the EDC interference, such as neurodevelopment and metabolic and cancer diseases [24], it is useful to schematize the following systemic adverse effects:

Metabolic alterations: resulting from the EDCs’ chemical interference [67, 68]; some POPs, BPA, and PhThs could interfere with the physiological processes of development, already in in utero life of adolescence, which would also depend on the time of exposure [14]. Obesity, in subjects up to 20 years of age, had been associated with prenatal and perinatal/infancy exposure to p,p’DDE, in a meta-analysis of prospective studies, which therefore confirmed previous similar evidence on individuals exposed to o,p’-DDT; later, also experimental analyses on animals highlighted this association [40].
Pituitary gland: may be impaired in its development and all aforementioned endocrine axis functions, with neuroendocrine control (initially neuronal and later endocrine), by those EDCs that have the ability to interfere with neurotransmitter receptors [24, 32, 69]; the consequences of these alteration vary, according to the endocrine system affected, with the central role of the hypothalamus [69]. For instance, a disruption in puberty central time and/or in the circadian rhythm can occur [32].
Thyroid gland: This involves possible compromises assuming the consolidated notion that indicates iodine as a basic component of thyroid hormones; the EDCs may interfere with thyrocyte activities and, especially by modifying the necessary channel to transport iodine in those cells, leads to a consequent reduction in the hormonal activity of the gland, with related hypothyroidism [32].

For example, a PFOA adverse outcome on the thyroid has been identified in rodents [42]. Further research is needed to evaluate the dose-effect relationship responsible for the effects of EDC interference and thyroid functionality [32, 48] and correlated Hg levels with the thyroid endocrine system [12].
Adrenal gland: Mostly for xenoestrogens, it is a preferential EDC target, due to its lipophilic structure on the cell membranes, the peculiar enzymatic activity, and the presence of a dense vascular network [32]. The main disrupted adrenal activity is correlated with HPA alterations also with the enzymatic function responsible for the steroid hormone production and every phase of steroidogenesis [24, 32, 70]. Adrenal interferences on its fetal time development are recognized congenitally also in adrenogenital disease occurring in the postbirth periods.
Brain development and behavior: In addition to what has already been reported, modifications evaluated, for instance, by one longitudinal research of groups of subjects at birth have been systematically studied for the possible association between neurodevelopment and EDCs, which could exert their endocrine interference on the individual already from his in utero life [47]; however, these systematic analyses are difficult due to the presence of incomplete side-by-side hardly comparable data, also following the review evaluation of over 100 papers where hypotheses on the consequences of PCBs pre-postnatal exposures have been investigated [47]. In addition, an evaluation, by magnetic resonance imaging of BPA effects on children brain white matters in utero exposed, gave evidence of a probable causal link; on the other hand, the results of these evaluations report consequences on childhood behavior, but extreme caution must be exercised in reading these data, even if specific questionnaires were validated [71, 72]. However, the study analyzed made it possible to list a sort of guideline to be applied when evaluating the cause-effect relationship between BPA pre-postnatal exposure and behavioral defects [72].
Cancers: The tendency to get sick with certain types of tumors could be related to noxious events during extremely sensitive periods of human life, such as embryo-fetal development and infancy [5, 19]. Moreover, the increased risk factors due to EDC exposure for hormone-dependent cancers are, for instance, around 90% of breast cancers could be related to the environment, with known probability [51], and prenatal exposure to exogenous estrogens had been documented as an element for the increased risk of breast and genital cancer [42].

A case-control retrospective analysis must be mentioned, in which Herbst and his group, in 1971, published a cluster of seven cases, affected by vaginal adenocarcinoma (clear and hobnail cells or endometrial type), in exposed young women to diethylstilbestrol (DES), during their intrauterine life; the association between the cancer and therapy was observed, with oral estrogens of their mother, prescribed for high-risk pregnancy, also underlined by the absence of pathology in the daughters of untreated women [73]. In this context, the concept of “diethylstilbestrol syndrome” was therefore also introduced to highlight the effects of each estrogenic chemical with antagonist capacity [12].

Generally, correlation data had and have been identified between exposure to EDCs and onset of tumor pathologies [14] also affecting prostate (As, Cd, pesticides, PCBs), testicles (also between As, Cd, PCBs, DDT, DDE, and PDBE with testicular dysgenesis syndrome (TDS)), thyroid (PCBs, biocides, pesticides, TCDD), and breast (PCBs, phytoestrogens, DES, Cd, dioxin) [24, 30, 32]; on the other hand, concrete association between thyroid and testicular tumors and EDC exposure is not possible, given the modest case studies [32].

9.3 States of EDC Science

It was the mid-1930s when a British medical researcher firstly, accidentally identified the estrogenicity of BPA, already synthesized in 1891, while attempting to find a synthetic estrogen agent, and earlier the endocrine-disrupting capacity of DDT and phenanthrene derivatives was discovered [74, 75]. Up to that historical moment, no chemically estrogen-like active substance, without the phenanthrene nucleus, had been identified [75]. On the other hand, subsequently, after some research years, the powerful estrogenic mother substance DES was obtained with particular methods, proving other evidence on ovariectomized rats [75]; by vaginal cornification test, DES had been classified as an estrogen-like substance, harder than BPA [75]. Afterwards, the first epidemiological research on female offspring patients, born between 1946 and 1951, was conducted for their vaginal cancers with anamnestic history of first-trimester in utero exposure to DES, administered to mothers, following the indications of high-risk pregnancy. This was the first association of cancer induced by prenatal contact with drugs endowed with the estrogenic capacity, as the current EDCs [73]. The potentially harmful substances, on animals and probably also on humans, were then evaluated, up to the formation of groups of interferers, to assess the scientific basis of risk from the ambient exposure to them. Continuing with some highlights, in 1997, the 50th World Health Assembly 50.13 included, among the strategic points to be developed, the following: “take the necessary action to strengthen WHO leadership in risk-taking evaluation as a basis for addressing emerging high-priority problems, and in promoting and coordinating correlated research, for example, on potential health related to the endocrine system effects to exposure to chemicals.” Thereafter, several aspects linked to the human and wildlife exposure to several compounds, single or mixed, were taken into consideration to evaluate their effects on several physiological body systems [20]. At that point, the definition of EDCs, since its basic formulation [3], has been well established by the WHO, since 2002, as “an exogenous substance or mixture that alters functions of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations” [20], as well as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action,” also indicated in the EC programmatic four options [76, 77]. As already mentioned above, the 2012 UNEP and the WHO became a milestone, publishing an update of the 2002 report of the International Programme on Chemical Safety (IPCS) [76, 78], noting the increase of endocrinal multicausal disorders also associated with exposure to EDCs, and recognizing the main sensitive human window—life (fetal, childhood, and puberty) of exposure [16, 23, 26, 54, 59].

In our time, different states which concern EDC science are at the global attention; nearly 86,000 toxic compounds [79] have been reported by the EPA in the Toxic Substances Control Act (TSCA) [46, 79]; the TSCA, which is a US law since 1976, had already defined the chemical substance “as any organic or inorganic substance of a particular molecular identity, including any combination of these substances occurring in whole or in part as a result of a chemical reaction or occurring in nature, and any element or uncombined radical,” and had already inventoried 62,000 compounds in 1982 [79]. The EPA has also formulated, and constantly updated and shared, the Endocrine Disruption Screening Program (EDSP), starting in 1996, based on research projects aimed at identifying guidelines for the main EDCs [24, 32, 80, 81]. Furthermore, the EU Commitment has therefore gradually intensified, under the Community Strategy for EDCs, with important advances in highlighting the mechanism of action of these molecules [26]. Currently, a systematically updated EDC list by the NIEHS is available which supports studies on the EDC mechanism of action that negatively affects human health, summarizing them as follows: (1) “decrease or increase normal hormone levels,” (2) “mimic the body’s natural hormones,” and (3) “alter natural hormone production” [29]. Moreover, the NIEHS has taken part in the Consensus on the EDCs’ specific key characteristics and coordinates projects in different research areas [14, 29]. On the other hand, extreme caution is required to evaluate in vitro/in vivo data, to be used as experimental evidences that can be translated to the human situation, also with the issue of analysis of the EDCs’ dose-response/duration of exposure and mechanism of action as interference with hormonal and enzymatic activity; for instance, some hypotheses published regarding the last aspect need to be deepened [46, 52]. Thanks to the research on animals, from which derive the most substantial data [36], and to human epidemiological results, which have made it possible to acquire the technical information available today, common guidelines can be defined to prevent EDCs’ effects, with the safe use of chemical compounds through shared monitoring systems [82]: with permission of the Endocrine Society. Hence, from the aforementioned epidemiological plus animal model studies, and the further known EDC definition as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action” [82], a relationship emerges between common noncommunicable disease and EDC levels, as well as doses, in the relative milieu [36, 82]. The scientific community does not yet report an unambiguous result on the EDCs’ non-monotonic dose-response/low-dose effects and their “safety threshold” [26]. However, thanks to the acquired knowledge, some of the mechanisms of action of EDCs have been detected on hormonal receptors of different types, on epigenetic modifications, and on transgenerational effects at different doses of endocrine-disrupting substances, underlining the foundations of scientific research on EDCs [14, 36].

Definition of a systematic scientific work on EDCs, the use of their KCs, and their transgenerational-epigenetic effects could be the starting point for weighing the risks associated with the exposure to that type of substance [14, 36].

Besides, the need to develop several appropriate and uniform testing methods is highlighted [26]. From the evidence that emerges, relating to a milieu of EDCs, there are possible associations between several adverse health outcomes, as well as interferences on sex hormones/receptors, reproductive mechanisms (as implantation/placentation) and thyroid [83, 84], and EDC exposure. Moreover, it was identified that several biological effects of EDCs are also mediated through the gene expression alterations, already mentioned as epigenetic modification effects in their three systems of action [36]. Experimental human research shows that pre- and postnatal exposure to EDCs, and/or a mixture of EDCs, may interfere with hormone axis with relatively negative effects on the male endocrine reproductive system; however, there are elements that make these studies limited and worthy of review on the EDC-level measuring methods, in relation to the different periods of the individual life [83]. The probable worrying and growing threat to environmental and human health, globally, could be determined by agricultural and industrial processes; therefore, other biomonitoring accurate systems will be needed [36]. To date, for example, starting from the lack of knowledge of the EDCs’ precise mechanism of interference with mammalian endometrium, a 2021 systematic review summarized the available studies, in vivo, in literature on the EDCs’ effects on mouse-model blastocyst-endometrial implant: following BPA and phthalate exposures, the detrimental alteration of implantation sites, receptivity endometrial markers, pregnancy hormone receptors, and pregnancy rates were highlighted [84]. Moreover, the same alteration was recorded in the adult age of the subjects who were in utero exposed to BPA [84]. On the other hand, the negative pregnancy issues, linked to the EDCs, seem to be related to both immature-mature and maternal-fetal side placental dysfunctions with alterations of the trophoblast cells’ metabolic capacity [62]. Recently, to deepen the study of the mechanisms that lead to these changes, the concept of “trophoblast organoid,” as an entity to be examined, has been introduced [62].

Already for years, there have been scientific evidences that would lead to the identification of urgent measures to reduce or avoid the exposure of EDCs, both temporally and quantitatively, also through the systematic monitoring of the potency of those substances, which could have an even more impact on human health, considering, moreover, the absence of a “safe dose” [59]. With regard to waste and harmful chemicals, in anticipation of the objectives until 2030, the Organisation for Economic Co-operation and Development (OECD) defines a “red light” matter that needs urgent application measures [59, 85].

Therefore, a common strategy was formulated, understood as the correlation between environment and public health, involving “global, regional, national, and local environmental factors, including external physical, chemical, and biological factors,” because the global objective is “a healthy environment vital to ensure healthy lives and promote well-being for all at all ages” [86, 87].

It will be appropriate to examine and investigate every aspect relating to the effects of any molecular endocrine disruptors, using standardized methods indicated by international guidelines, also for drinking water [36, 88].

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The Residency School of Specialization in Obstetrics and Gynaecology, University of Padua, Padua, Italy
Maria Laura Solerte & Erich Cosmi
Department of Woman and Child Health, University of Padua, Padua, Italy
Erich Cosmi
The Maternal and Fetal Medicine Unit for High-Risk Pregnancies, Padua Hospital, University of Padua, Padua, Italy
Erich Cosmi
Midwifery School, Faculty of Medicine, University of Padua, Padua, Italy
Erich Cosmi

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Roberto Marci

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Solerte, M.L., Cosmi, E. (2023). Endocrine-Disrupting Chemicals and the Offsprings: Prenatal Exposure. In: Marci, R. (eds) Environment Impact on Reproductive Health. Springer, Cham. https://doi.org/10.1007/978-3-031-36494-5_9

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Endocrine-Disrupting Chemicals and the Offsprings: Prenatal Exposure

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