The Role of Environmental Pollution in Endocrine Diseases

  • Agostino Di CiaulaEmail author
  • Piero Portincasa
Living reference work entry
Part of the Endocrinology book series (ENDOCR)


Environmental pollution is able to affect the balance of multiple endocrine axes in humans. This negative outcome occurs because of the effects of artificial chemicals, which are widely diffused. The endocrine-disrupting chemicals (EDCs) are ubiquitous and are able to mimic hormones, to block hormones, or to modulate their synthesis, metabolism, transport, and action. In this scenario, these chemicals represent a threat not only to individual but also to global health. The exposure to EDCs starts very early in life (in utero life), is able to modulate epigenetic mechanisms, and has a lifelong duration. The exposure interacts with other effects on health, which originate from other pollutants, and affect several vital functions of the body, which also include a correct development. Mechanisms of damage can therefore range from intracellular molecular alterations to disrupted multiorgan endocrine homeostasis. The interest for the endocrine-mediated health effects of environmental chemicals (mainly insulin resistance, obesity, type 2 and type 1 diabetes, thyroid diseases, reproductive abnormalities, cancer) is growing. The concern is due to the large and increasing burden of such compounds in the environmental matrices (air, water, soil), in the food chain, and in consumer goods used daily. Additional aspects to consider include the well-documented links with a number of diseases at increasing incidence, and the high direct and indirect health costs generated by the exposure to EDCs worldwide. EDCs can act at very low doses and according to nonmonotonic dose-response curves. Relevant aspects also derive from the possible transgenerational effects due to maternal exposure during pregnancy and/or to paternal preconceptional exposure, with possible risk of developmental alterations and diseases appearing later in life. Further studies are urgently required to explore even better the combined effects of the exposure to multiple EDCs, the effects in individuals characterized by variable susceptibility, the epigenetic mechanisms, and the transgenerational effects, including cancer risk. There are abundant available evidences, however, to promote adequate primary prevention policies. Actions should focus to strongly limit the environmental burden of EDCs and to decrease the epidemic growth of noncommunicable diseases while reducing the relevant health costs secondary to exposure.


Endocrine-disrupting chemicals Pollution Environment Epigenome 


Endocrine-disrupting chemicals (EDCs) represent a large class of artificial and ubiquitous compounds. EDC are able to mimic with an agonist-like effect, to block with an antagonistic-like effect, or to modulate, i.e., reducing or increasing the synthesis, the metabolism, and the action of hormones.

EDCs with their wide mechanisms of action represent a threat not only to individual but also to global health.

In the document titled “Global Assessment of the State-of-the Science of Endocrine Disruptors” (, year 2012), the WHO – International Programme on Chemical Safety (IPCS), the United Nations Environment Programme (UNEP), and the International Labour Organization defined the EDCs as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations.

The environmental matrices (air, soil, and water), the food and the majority of daily used products, contain hundreds of chemicals, including unintentional contaminants, with well-known or potential (i.e., still undetermined) endocrine-disrupting effects.

According to the United Nations Environment Programme (UNEP), the size of global chemical industry exceeded 5 trillion USD in 2017, and is going to double by 2030. This worrisome trend depends mainly from the emerging economies, which are characterized by the rapid increase of consumption and production. As a consequence, hazardous chemicals and pollutants are released in large quantities in the environment, are ubiquitous in humans, and accumulate in the food chain, in material stocks and products.

Data compiled by the European Environment Agency (year 2018) show that approximately 62% of the total volume of chemicals consumed in Europe in 2016 was hazardous to health, and the 2017 report of the Lancet Commission on Pollution and Health identified chemical pollution as a significant and “almost certainly underestimated” contributor to the global burden of disease.

The EDCs, in particular, belong to a large group of chemicals, which are of artificial origin in most cases. Substances exist in a number of materials of daily use, in food and water, and are widely distributed in the environment as agricultural products including pesticides, herbicides, insecticides, phytoestrogens, and fungicides. Substances also are present in emissions deriving from combustion processes (mainly transport vehicles and industrial burning of fossil fuels, waste or biomasses: dioxins, PCBs, alkyl phenols, heavy metals, particulate matter, gaseous pollutants), in consumer products (i.e., plastics, food processing/storage, home products, building materials, and personal care products: phthalates, polybrominated biphenyls, bisphenol A), and in pharmaceuticals (such as parabens) (Table 1).
Table 1

The most widely diffused endocrine-disrupting chemicals (EDCs), grouped according to source of exposure



Industrial origin, combustion processes:


2,3,7,8-Tetrachlorodibenzo para dioxin (TCDD); polychlorinated dibenzo para dioxins (PCDD); polychlorinated dibenzofurans (PCDF)

Widely diffused and mainly unwanted by-products of industrial processes as smelting, chlorine bleaching of paper pulp, industrial/municipal waste incineration, manufacturing of herbicides and pesticides.

Dioxins are found in soils, sediments, and food (dairy products, meat, fish, and shellfish). Very low levels are found in plants, water, and air. Thus, the main routes of introduction in the human body are ingestion with contaminated food and dermal contact, although inhalation is also possible.

Concerns derive from their highly toxic potential, from the long time they last in the body (fat tissue, prolonged half-life), from their chemical stability (persistence in the environment), from the tendency to accumulate in the food chain, and to biomagnification. They also cross the placenta, are excreted in breast milk, and accumulate in the fetus/infant.

Polychlorinated biphenyls (PCBs)

Synthetic chlorinated hydrocarbon compounds. Produced commercially since 1929, PCBs have been used in plasticizers, surface coatings, inks, adhesives, flame retardants, pesticide extenders, paints, and microencapsulation of dyes for carbonless duplicating paper, dielectric fluids in transformers, and capacitors.

Their production has been severely restricted or banned in many countries. However, PCBs are frequent unwanted by-products of industrial combustion processes. Their toxicity and physical and chemical properties are similar to dioxins.

Exposure is commonly to mixtures of PCBs and the toxicity level is also depending from the sum of congeners and from the relative prevalence of different congeners. Humans may be exposed to PCBs by inhaling contaminated air and/or ingesting contaminated water and food.


Chemical anion widely contaminating food and water, and occurring from both anthropogenic and natural sources. Man-made perchlorate has been used in a number of products including missile fuel, fireworks, vehicle airbags, fertilizers.

This substance is highly persistent in the environment and can accumulate in water, soil, and vegetables. Human exposure is through ingestion of contaminated water and food (dark leafy green vegetables, milk products, meat, fruits, eggs), but also from inhalation (occupationally exposed workers).

Heavy metals (i.e., cadmium, lead, mercury, arsenic)

Environmental contamination by heavy metals (soil, water, food) can derive from a number of industrial, agricultural, pharmaceutical, or domestic sources.

Mining, refineries, coal burning (power plants), oil combustion, biomass combustion, waste incineration, paper processing plants, cement plants, foundries and smelters, and other metal-based industrial activities generate air pollution by heavy metals, which can be variably vehiculated by particulate matter.

Heavy metals can be introduced in the human body through inhalation, ingestion of contaminated food/water, or dermal contact.

Air pollutants

Air pollution is a heterogeneous mixture of gases and solid particles, each component having potential effect on the human body.

Particulate matter (PM) is composed by solid particles of different composition and size ranging from nanometric scale up to tens of micrometers. Particles with a diameter less than or equal to 2.5 μm, when inhaled, penetrate deeply (lower airways) and are able to cross the blood-lung barrier, producing negative effects at a systemic level.

The health hazards of PM are inversely proportional to the diameter of particles and directly proportional to their concentration or, in the case of ultrafine particles, to their number. No apparent threshold exists below which the association between the air concentration of PM and adverse health effects no longer applies, and fine/ultrafine particles are able to cross all anatomic and functional barriers, including the blood-brain barrier and the placenta.

Particles with the highest toxicity are generally produced by combustion processes (motor vehicles, industrial procedures processing, and/or burning fossil fuels, biomasses, or waste).

Polycyclic aromatic hydrocarbons (PAHs)

A mixture of chemical compounds produced after combustion processes involving fossil fuels, wood, waste, biomasses, tobacco. High-temperature cooking also generates PAHs in foods. PAHs are usually introduced in the human body through contaminated air (inhalation), contaminated food (ingestion), or dermal contact.

Agricultural origin:

Pesticides, herbicides, fungicides

A large group of chemical compounds widely diffused in the environment to kill pests and unwanted plants. By their nature, these compounds are potentially toxic to other organisms, including humans, and can have acute and chronic health effects when introduced in the human body through inhalation, ingestion (contaminated food/water), or dermal contact.

Some pesticides can be particularly persistent in the environmental matrices (soil, water) and almost all can enter the food chain. They are able to cross the placenta and all anatomic and functional barriers, including the blood-brain barrier. Children and exposed workers are particularly vulnerable subjects.


Plant-derived dietary compounds (mainly isoflavones, prenylflavonoids, coumestans, and lignans) with structural similarity to the primary female sex hormone 17-β-estradiol (E2). These chemical compounds can be found in a variety of foods and, in particular, in soy and legumes.

Residential origin:

Food processing, home products, dressing, personal care, building materials.


Plasticizers and softeners present in various commercial products including food packaging, building materials, toys, medical devices, cosmetics.

Easily transferred to indoor dust, air, food, water. Introduced in the human body are rapidly metabolized and metabolites are excreted with urine and feces.

Urinary metabolites are generally employed as biomarkers of exposure in humans.

Polybrominated diphenyl ethers (PBDEs)

Flame retardants used in a number of consumer products including electronic devices (i.e., cell phones, remote controls, computers), automotive products, textiles, foam-based packaging materials, carpet padding, paint products, adhesives.

PBDEs can be introduced in the human body through inhalation, dermal contact (air, soil, house dust, PBDEs containing objects), or by ingestion of contaminated food (in particular high-fat foods and fish) and water. PBDEs can be transmitted through breast milk and children are particularly vulnerable.

Bisphenol A

Plasticizer used in the manufacture of polycarbonated plastics and epoxy resins. Exposure mainly through plastic food containers, canned food, baby formula cans, carbonless print paper, medical devices, home dust.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS)

Chemicals employed in the production of a number of items resistant to heat, oil, grease, and water. The widespread and long-lasting use of these man-made chemicals (nonstick cookware, fabric, food packaging, industrial processes, fire-fighting foam) has generated a global contamination of water.

The more represented compounds (perfluorooctane sulfonate, PFOS; perfluorooctanoic acid, PFOA; perfluorohexane sulfonate, PFHxS) are persistent in the environment and can persist for a long time in human tissues, generating health effects.


Organic chemicals of industrial origin obtained by alkylation of phenols. The term is usually reserved for commercially important propylphenol, butylphenol, amylphenol, heptylphenol, octylphenol ethoxylates (OPEs), nonylphenol ethoxylates (NPEs), dodecylphenol, and related long-chain alkylphenols (LCAPs).

Substances are used in the production of lubricating oil additives, detergents, pesticides, laundry and dish detergents, emulsifiers, solubilizers, and in the processing of wool and metals, manufacture of thermoplastic elastomers, antioxidants, and fire retardants.

Human exposure to alkylphenols is mainly dependent on the ingestion of contaminated foods and drinking water and, to a lesser extent, to inhalation (octyphenol).



Chemicals widely used as preservatives in the cosmetic, food, and pharmaceutical industries. The most commonly used parabens are methylparaben and propylparaben.

Ethylparaben, butylparaben, and benzylparaben are particularly employed in antimicrobial mixtures. These compounds exhibit antimicrobial and estrogen-like activity proportionally related with the length of the alkyl substituent. Exposure to parabens usually occurs through ingestion, cutaneous absorption, and inhalation, and these chemicals may accumulate in the body.


Lipid-soluble antimicrobial agent commonly used for hand and body washes, in toothpastes, personal care products, household products, textile goods. Its widespread use since decades has generated a worldwide contamination of the aquatic environment.

Exposure is mainly through direct contact with triclosan-containing products (ingestion and dermal absorption), but also secondary to the widespread contamination of environmental matrices (water, soil) and other organisms. Triclosan has been detected in breast milk.

Exposure to the majority of EDCs is widespread and in humans could be responsible for a variety of pathologic conditions such as metabolic disorders, cancer, reproductive disorders, malformations, neurologic diseases, and altered development.

In consideration of the available scientific data deriving from in vitro evidences, animal and human studies, and from epidemiologic analysis, EDCs generate growing concerns due to their relationships with the high and increasing incidence of some endocrine disorders in humans (Table 2), and to increasing evidences of abnormal endocrine effects in wildlife populations.
Table 2

Epidemiologically rising endocrine-related disorders possibly linked to EDCs

Low semen quality in young men (reduction in sperm cell count, impaired sperm cell motility, abnormal sperm cells)

Genital malformations in males (mainly cryptorchidisms, hypospadias)

Altered reproductive function in females

Adverse pregnancy outcomes (preterm birth, low birth weight, spontaneous abortion, stillbirth)

Thyroid diseases

Endocrine-related cancers (breast, endometrium, prostate, testicular, thyroid)

Obesity in adults and in pediatric age

Metabolic syndrome

Fatty liver disease and nonalcoholic steatohepatitis

Type 2 diabetes

Type 1 diabetes

The socioeconomic cost of health effects associated with hormone-disrupting chemicals could range, in Europe, approximately between 46 and 288 billion euros per year (RiJk et al. 2016). Experts calculated that the cost related to EDCs in the year 2010 was much higher in USA ($340 billion, corresponding to 2.33% of the gross domestic product) than in Europe ($217 billion, 1.28% of the GDP), and this trend was mainly driven by neurocognitive effects as loss of IQ points and intellectual disability (Attina et al. 2016).

Several possibilities exist to come across EDCs. Substances can enter the human body through dermal contact and cutaneous absorption, as well as during ingestion of contaminated food and water (i.e., components of plastics or consumer goods, chemicals of industrial and agricultural origin) and also during breathing air (in the form of gaseous pollutants and particulate matter).

Once introduced into the body, EDCs are able to interfere either directly or through their metabolites with multiple endocrine pathways. EDCs can also negatively affect vital functions such as cell cycle, reproduction, development and growth, metabolism, immunity, and behavior.

EDCs can act on endocrine organs and cells causing anatomical and/or functional alterations leading to impaired hormone synthesis and secretion. They are able to modulate, also at low doses (part-per-trillion to part-per-billion range), more than a single axis/organ, mainly acting on the hypothalamus-pituitary gland-thyroid, hypothalamus-pituitary gland-gonads, hypothalamus-pituitary gland-adrenal axes.

EDCs can also induce negative effects on adipogenesis, liver, pancreatic and neurologic function, and gut microbiota.

EDCs can bind nuclear receptors and can induce defective hormone transportation (altered binding to carriers). Furthermore, at the level of target tissues, EDCs may present hormone-mimetic effects (receptor agonism) or receptor antagonism, can alter the amount of available receptors, are potentially able to disrupt hormone metabolism and to modulate genomic expression (Fig. 1).
Fig. 1

Major mechanisms of action of endocrine-disrupting chemicals (EDCs). Once entered into the human body mainly through cutaneous absorption, breathing (air pollution), and/or ingestion (contaminated food/water), EDCs can act directly and/or through their metabolites at different levels. (1) At the level of endocrine gland/cells, EDCs are able to induce anatomical alterations (hypotrophy, hypertrophy, atrophy, altered histology). Consequences include effects on cell functions, metabolism, and viability (binding to nuclear receptors, oxidative stress, induction of cell apoptosis), can affect physiological mechanisms leading to hormone synthesis and/or secretion, and can alter gene expression, mainly through epigenetic mechanisms (i.e., DNA methylation, hystone deacetylation, noncoding microRNA). (2) The transportation process from the site of hormone synthesis/secretion to target tissue(s) can be affected due to altered conjugation processes (sulfation and glucuronidation) and/or altered binding of hormones to carrier proteins. (3) In target tissues, EDCs can interfere with the physiologic hormone actions due to hormone-mimetic effects (receptor agonism) or to receptor antagonism, but can also alter the concentration of hormone receptors (e.g., secondary to altered gene expression) and/or affect the metabolism or catabolism of hormones. Finally, EDCs are able to alter genomic expression, mainly due to epigenetic mechanisms. Due to this last effect and to the capacity to cross the placental barrier, maternal exposure to EDCs can generate transgenerational effects and fetal programming, with transmission of the risk in the offspring and possible late onset of disease

Due to their particular chemical and physical properties, some EDCs (the persistent organic pollutants, POPs) are generally persistent in the environment and are able to induce bioaccumulation and biomagnification through the food chain. Humans live at the top of the food chain and therefore show the highest concentrations of EDCs in body tissues, blood, and urine.

Several mechanisms of actions may explain the biological and clinical consequences deriving from EDCs exposure. The consequences could be due to the variable combination of multiple chemicals producing cumulative, additive, and synergic effects.

Substances may act with similar mechanisms of action, after low-dose chronic exposure, and according to individual vulnerabilities (i.e. professional workers, perinatal period/childhood, gene polymorphisms).

Factors to consider are also the timing of exposure (most dangerous effects generally seen after lifelong exposure starting very early) and the possibility of promoting transgenerational effects.

Pregnant women and children are highly vulnerable subjects, and the majority of EDCs are transmissible through the placental barrier and breast milk, with significant consequences during in utero life and in the perinatal period. A number of effects, however, might become evident later in life, mainly as noncommunicable diseases.

Embryo, fetus, newborns, and children are particularly susceptible to EDCs because these chemicals have the capacity of affecting the endocrine homeostasis and, in turn, to influence a correct development. Furthermore, children are more exposed to EDCs than adults due to their hand-to-mouth activity and to their higher metabolic rate.

A crucial aspect determining the toxic potential of EDCs is that these chemicals can be hazardous also at very low doses. A low dose effect, in particular, is defined as any biological change occurring in the typical range of human exposures, or biological changes occurring at doses below those used in traditional toxicological studies.

A number of evidences indicate that low dose effects exist and are reproducible for several EDCs. Furthermore, biochemical, animal, and human studies suggest that EDCs frequently have nonmonotonic dose-response curves (Fig. 2). As a consequence, low concentrations may be more harmful than higher concentrations. The presence of a nonmonotonic relationship between chemical dose and an adverse outcome might have relevant implications in regulatory decisions. In this case, in fact, the classical toxicological extrapolation (i.e., based on linear models) from high “toxic” doses to lower “safe” doses, should not be applied. Thus, clinical effects induced by EDCs can occur below the toxicologically assessed no-observed-adverse-effect level (NOAEL) and, in general, below the reference dose generally considered as “safe” simply extrapolating it by linear models.
Fig. 2

Examples of monotonic or nonmonotonic responses to variable doses of toxic chemicals. In the case of a monotonic response (left graph), the toxicologic principle “the dose makes the poison” (the greater the dose, the greater the effect) is valid. The relationship can be linear of nonlinear but the response curve moves along an upward diagonal from left to right (monotonic response). Conversely, in the case of a nonmonotonic effect (right graph), there is a change in the sign (positive/negative) of the slope of a dose-response relationship over the range of doses tested. In this example of nonmonotonic effect, a “U” shaped curve is depicted. In the case of EDCs, a number of in vitro, animal, and human studies identified nonmonotonic dose-response effects following exposure

Growing interest also derives from the ability of EDCs to modulate epigenetic alterations (mainly histone modifications, DNA methylation, noncoding micro-RNAs, chromatin structure, and RNA methylation) altering the expression of the genome, without modifying the sequence of the genes.

Epigenetic changes involving the germline (sperm, egg) can be inherited between generations, promoting phenotypic variations or diseases without a direct exposure.

Thus, as an effect of epigenetic modulation, mother’s exposure during pregnancy can lead to transgenerational effects and fetal programming, with risk transmission through successive generations also in the absence of direct exposure of the offspring. These processes are involved in the reprogramming of primordial germ cells during gonadal development and in the onset of diseases during childhood, adolescence, or adult age, underlying the importance of developmental factors in influencing the risk of later-life disease.

Insulin Resistance, Obesity, Type 2 Diabetes

Diseases linked with insulin resistance (i.e., overweight, obesity, type 2 diabetes mellitus, liver steatosis, nonalcoholic steatohepatitis, metabolic syndrome) are rapidly growing worldwide. These conditions generate great concern because they are risk factors for cardiovascular disease and cancer, and because they produce high health costs in every national health system.

The incidence of obesity, in particular, is continuously increasing in both adults and children without evident reversal trend, and independently from the adoption of specific policies to prevent the obesity epidemic in a growing number of countries.

According to the World Health Organization, worldwide obesity has almost tripled since 1975, with more than 1.9 billion adults being overweight, over 650 million adults being obese, 41 million children under the age of 5, and 340 million children and adolescents aged 5–19 years being overweight or obese in the year 2016.

Similarly, the number of subjects with type 2 diabetes has risen from 108 million in 1980 to 422 million in 2014, with a global prevalence that increased in adults from 4.7% in 1980 to 8.5% in 2014.

Such epidemiologic variations seem to be partly independent from genetic factors (i.e., the genetic risk depending on single-nucleotide polymorphisms and predisposing to disease onset and progression). Although genetic susceptibility has a key role in the determination of obesity and type 2 diabetes, the epidemiological variations observed in the last decades are too rapid to be explained simply on a genetic basis. In a large sample of US subjects born between 1901 and 1986 and aged 25–64.9 years at the time of measurements (Fels Longitudinal Study), the obesity rate increased according to birth year, but the score measuring the genetic risk of developing obesity (32 well-replicated obesity-related common single-nucleotide polymorphisms) remained stable (Demerath et al. 2013).

On the other hand, growing evidences point to a major role for environmental factors in the determination of disease onset. Factors include lifestyles (diet, physical activity), maternal dietary factors, direct effect of food on gut microbiota, ingestion of toxic chemical contaminants with food/water, air pollution. Gene-environment interactions play a role also following early (in utero) exposure, in particular in the case of visceral fat disorders, obesity, and insulin resistance (Di Ciaula and Portincasa 2014, 2017).

Differences in national and local environments could contribute to variable obesity prevalence across countries. However, at the global level, during the past 4–5 decades, modifications in lifestyle and in the food system, industrial processes (in particular industrial combustions, food management and packaging, global chemical industry), and deterioration of the environmental matrices (air, soil, water) have created an “obesogenic” environment certainly contributing to the increase of the obesity epidemic.

In this scenario, EDCs play a critical role, since they are able to alter metabolic pathways and energy intake, production, storage, and use through multiple mechanisms. Steps include modulation of neuronal behavior which control food intake, altered composition of the intestinal microbiota, altered gut permeability, disrupted pathways regulating gastrointestinal peptides, altered gene expression, impaired modulation of key enzymes, altered hormonal homeostasis (e.g., insulin, thyroid hormones), disrupted signaling pathways, and levels of adipokines essential for the metabolic and energetic balance.

The combined effects of EDCs on various organs (i.e., brain, liver, pancreas, gut, skeletal muscle, adipose tissue) can lead to a disruption of mechanisms regulating energy storage, and the effects on skeletal muscle and on thyroid hormones are able to affect energy output.

EDCs can influence glucose and lipid metabolism and, in turn, pathogenic mechanisms leading to insulin resistance, obesity (in both children and adults), and type 2 diabetes.

The obesogenic properties of EDCs primarily derives from their ability to affect pathways linking multipotent stromal stem cells to mature adipocyte, and involving peroxisome proliferator-activated receptor γ (PPARγ), epigenetic factors (as increased histone deacetylation and altered DNA methylation), and other mechanisms finally leading to increased adipocyte formation and increased fat storage (Di Ciaula and Portincasa 2014, 2017).

The adipose tissue is a target for several lipophilic EDCs, with significant consequences in terms of co-contamination, altered metabolic homeostasis, and impaired endocrine function of the pancreas (Di Ciaula and Portincasa 2014, 2017).

Persistent organic pollutants (POPs), in particular, are a group of several hundred halogenated compounds (i.e., dioxins, furans, polychlorinated biphenyls, organochlorine pesticides) characterized by their high lipid solubility. These organic chemicals are generally persistent in the environment and are able to enter the food chain and to accumulate in the human body, producing toxic effects also after chronic exposure to low concentrations. After ingestion of contaminated food (in particular fish, eggs, meat, milk), POPs are stored in visceral adipose tissue, with a trend increasing with age, and with specific relationships with insulin resistance, with obesity, and with components of the metabolic syndrome (Di Ciaula and Portincasa 2014, 2017).

On the other hand, storage of POPs in the adipose tissue (i.e., during weight gain) could reduce the burden of these chemicals in other organs. This possibility represents a protective factor against endocrine, immunologic, neurologic, and reproductive effects. POPs stored in the adipose tissue, however, might also represent a condition predisposing to their release from adipose tissue during weight loss or in the case of insulin resistance because of increased lipolysis. The resulting increment of the amount of POPs in the circulation can therefore imply a less efficient metabolism and clearance of these toxics, with higher possibility to reach critical organs such as brain, liver, kidneys, and reproductive organs.

POPs have also relevant implications in terms of transgenerational transmission of risk. High serum concentrations of persistent organic pollutants (mainly PCBs, the organochlorine pesticides dichlorodiphenyldichloroethyle [DDE], and hexachlorobenzene [HCB]) in women in the first trimester of pregnancy have been related, in offspring (4 years of age) with higher BMI z-score and obesity (Vafeiadi et al. 2015).

In a Scandinavian prospective study on a cohort of 412 pregnant Norwegian and Swedish women, maternal serum concentrations of perfluorooctane sulfonate (PFOS) at 17–20 weeks of gestation were linked with increased BMI-for-age-and-sex z-score and with increased triceps skinfold z-score in children at 5-year follow-up. In the same cohort, maternal serum perfluorooctanoate (PFOA) concentrations were significantly linked with child overweight/obesity. Of note, the authors described evidences for a nonmonotonic dose-response relationship between PFOS and child overweight/obesity (Lauritzen et al. 2018).

Bisphenol A (BPA) (Fig. 3), a widely diffused food contaminant, is employed in the manufacture of polycarbonate plastic and epoxy resins, and contaminates food and beverages leaching out from containers. The body concentrations of BPA have been specifically linked with obesity, weight gain, and type 2 diabetes.
Fig. 3

Chemical structures of Bisphenol A, Bisphenol S, and Bisphenol F. Bisphenols are organic synthetic compounds with two hydroxyphenyl groups. Bisphenol S (BPS) has two phenol functional groups on either side of a sulfonyl group. In Bisphenol F (BPF), the two aromatic rings are linked by a methylene-connecting group. Bisphenol A (BPA), a widely diffused food contaminant, is mainly employed in the manufacture of polycarbonate plastic (e.g., water bottles, sport equipment, CDs, DVDs, and a number of other common consumer goods) and epoxy resins (water pipes, coatings on the inside of food and beverage cans, thermal paper). Due to its well-known hazardous endocrine-disrupting activity and to the widespread contamination, BPA has been banned in several products, mainly being substituted by the analogues BPS and BPF. However, growing evidences deriving from in vitro, animal studies, and epidemiologic surveys raised concerns for the safety also in the case of these two analogues

Recently, in children aged 6–18 years, urine concentration of BPA in the third tertile was linked with a 12.5 times higher risk of obesity (Amin et al. 2019).

In USA, BPA exposure has been linked with the onset of 12,404 cases of childhood obesity in the year 2008, and it has been estimated that removing BPA from food could prevent 6236 cases per year, with great economic benefits (Trasande 2014).

There are evidences that, during pregnancy, exposure to BPA generates a rise in the risk of childhood obesity ranging from +20% to +69%. This change would cause 42,400 new cases per year, with associated lifetime costs of € 1.54 billion. Adult obesity linked to phthalate exposure is the second largest driver of costs (€ 15.6 billion per year) (Trasande et al. 2015).

Due to the well-known endocrine-disrupting effect of BPA, this chemical has been banned in a number of products, and has been widely substituted with the analogues Bisphenol F (BPF) and Bisphenol S (BPS). However, a number of preliminary results mainly deriving from in vitro and animal studies raised concerns for the safety of these two analogues.

A large USA epidemiologic study carried out in adults (1521 participants from the National Health and Nutrition Examination Survey 2013–2014) assessed the urinary concentration of BPA, BPF, and BPS. The study confirmed the presence of a significant association between BPA exposure with general and abdominal obesity but failed to demonstrate a significant association in the case of BPF or BPS (Liu et al. 2017). Conversely, a recent and large epidemiologic study in children and adolescents has shown that, in these class ages, BPF was positively linked with higher risk of obesity (Liu et al. 2019).

Phthalates (Fig. 4) are extensively used in plastics to increase their flexibility. Phthalates are mainly introduced with contaminated food migrating from containers. A twofold increase in phthalate exposure has been described as a consequence of diets high in meat and dairy consumption. Phtalates are also detectable in infant formulas, wines, and grape spirits, with metabolic effects similar to those induced by BPA and depending from the ability to regulate the expression of genes involved in adipocyte differentiation and adipogenesis, and to the involvement in a number of metabolic processes (Di Ciaula and Portincasa 2017).
Fig. 4

Chemical structures of the phthalates bis(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP), and di-isodecyl phthalate (DIDP). DEHP (diester of phtalic acid and the branched-chain 2-ethylhexanol) is the most common chemical in the group of phthalates. Phtalates, widely used in plastics to increase flexibility, can migrate into food from containers. These endocrine-disrupting chemicals are extensively used in industrial products (i.e., adhesives and sealant chemicals, intermediates, plasticizers), in home products, and in consumer goods (i.e., adhesive and sealants, arts, crafts and hobby materials, construction materials, electrical and electronic products, fabric, textile and leather products, lawn and garden care products, paints and coatings, plastic and rubber products, toys, playgrounds, and sporting equipment)

An analysis of data from NHANES (766 children, age range 12–19 years) showed a direct relationship between levels of diethylhexyl phthalate (DEHP) metabolites and insulin resistance, with a 0.27 increase in the HOMA-IR for each log (roughly threefold) increase in DEHP metabolites. The prevalence of insulin resistance in the study population was significantly lower (14.5%) in the first tertile of DEHP metabolite than in the third tertile (21.6%) (Trasande et al. 2013). Similarly, urinary concentrations of di-isononyl phthalate (DINP), proposed as substitute of DEHP and commonly found in processed food, have been linked with increased insulin resistance in a cross-sectional study in adolescents from the 2009–2012 NHANES cohort (Attina and Trasande 2015).

Only in the European Union, researchers have estimated that exposure to phthalates can increase the risk of obesity and diabetes by 40–69%, with 53,900 cases of obesity and 20,500 new cases of diabetes in older women each year (Trasande 2014).

Animal and human studies point to specific relationships between the exposure to organophosphate and organochlorine pesticides also during pregnancy, and metabolic abnormalities, including obesity (Di Ciaula and Portincasa 2017).

Furthermore, glyphosate, the most popular herbicide used worldwide, affects the expression of genes involved in the adipogenesis, due to the induction of PPAR gamma and to oxidative stress (lipid peroxidation), altering cellular physiology (Martini et al. 2016).

Gut microbiota is emerging as a critical factor in the complex pathways determining the risk of metabolic disorders as obesity and type 2 diabetes, mainly through the production of short-chain fatty acids, which are able to act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) at various levels (brain, peripheral nerves, muscle, liver, gut), modulating the metabolic homeostasis.

Intestinal microbiota can also act through epigenetic mechanisms (mainly inhibition of histone deacetylase activity) able to modulate gene expression and to favor the onset of metabolic disorders, including obesity (Kasubuchi et al. 2015).

On the other hand, gut microbiota is the first exposure site after the ingestion of contaminated food, thus playing a key role in the subsequent toxic effects, which can include gut dysbiosis.

Chlorpyrifos, a widely diffused pesticide, when ingested with contaminated food can alter the composition of gut microbiota, thus altering its influence on metabolic processes and modulating pathogenic mechanisms leading to obesity and insulin resistance.

It has been shown that exposure to organochlorine pesticides (cis-nonachlor, oxychlordane, and trans-nonachlor) is linked with the amount of methanobacteriales which, in turn, is related with higher body weight, waist circumference (Lee et al. 2011), and obesity (H. Zhang et al. 2009).

Besides pesticides, several animal studies also described altered gut microbiota following ingestion of heavy metals (in particular arsenic, lead), BPA, phthalates, parabens, and triclosan.

A meta-analysis examining 41 cross-sectional and 8 prospective studies in ethnically diverse populations showed that serum concentration of dioxins, PCBs, and chlorinated pesticides had a significant relationship with the risk of type 2 diabetes, with pooled relative risks (RR) of 1.91, 2.39, and 2.3, respectively. An association with type 2 diabetes was also shown for urinary concentrations of BPA and phthalates (pooled RR 1.45 and 1.48, respectively) (Song et al. 2016).

Analysis of data from the National Health and Nutrition Examination Survey (NHANES) 2007–2010 revealed, in the general US population, a significant dose-response relationship between urinary concentration of 3-phenoxybenzoic acid (3-PBA, the most common metabolite of pyrethroids, widely diffused insecticides) as quartile and prevalent diabetes, after adjusting for confounders (Park et al. 2018). Furthermore, according to data from the Agricultural Health Study (13.637 subjects), the use of three organophosphate pesticides (fonofos, phorate, parathion), the organochlorine pesticide dieldrin, and the herbicide 2,4,5-T/2,4,5-TP were positively associated with incident diabetes (Starling et al. 2014).

Of note, the obese phenotype could also derive from epimutations (i.e., epigenetic alterations in parental sperm and egg) inheritable in future generations. A recent animal study showed that a transient exposure to a dose of glyphosate (a widely diffused herbicide) corresponding to half of the NOAEL in gestating F0 generation female rats during days 8–14 of gestation, caused a significant increase in the obese phenotype of the F2 (grand-offspring) and F3 (great-grand-offspring) glyphosate lineage males and females, as compared with control lineage offspring. In particular, a transgenerational (F3 generation) obese phenotype was observed in approximately 40% of the glyphosate lineage females and 42% of the glyphosate lineage males. These results were attributable to epigenetic inheritance (altered DNA methylation) in the glyphosate lineage sperm in the direct exposure F1 and F2 generations, as well as in the transgenerational (and nondirectly exposed) F3 generation (Kubsad et al. 2019).

EDCs can also be introduced by breathing, as a consequence of air pollution.

Several evidences indicate that, besides the well-known respiratory, cardiovascular, neurologic, and oncologic effects, air pollution (mainly in term of air concentration of nitrogen dioxide, particulate matter, and polycyclic aromatic hydrocarbons) is also able to promote insulin resistance and, thus, can be considered a risk factor for obesity and for the onset of type 2 diabetes and its complications.

The major mechanisms linking atmospheric pollutants with metabolic disorders are the promotion of oxidative stress, the modulation of epigenetic mechanisms (mainly DNA methylation), and, probably, alterations in gut microbiota.

Exposure to particulate matter (PM10) and nitrogen dioxide has a relationship with the onset of insulin resistance in school-aged children, even at concentrations of pollutants much lower than those allowed by current legislation (Thiering et al. 2013).

It has been also shown that mother’s exposure to nitrogen dioxide and PM2.5 (fine particulate matter) during pregnancy is linked with an increment of adiponectin levels in umbilical cord blood, with possible negative effects on the metabolic homeostasis in the fetus (Lavigne et al. 2016). Similarly, the exposure of pregnant mothers to polycyclic aromatic hydrocarbons increases the risk of obesity in children (Rundle et al. 2012).

On the other hand, the role of fine particulate matter in increasing the mortality due to diabetes has been known for a long time. As has been shown in a large Canadian prospective cohort study (2.1 million adults), the risk for diabetes-related mortality increases 1.49 times for each 10 μg/m3 increase in atmospheric concentrations of PM2.5, and persists for concentrations below 5 μg/m3 (Brook et al. 2013).

Type 1 Diabetes

The incidence rate of type 1 diabetes (T1D) in pediatric age has doubled over the last 20 years, with a 3.4% increase per annum. The progression of this epidemiological trend during a relatively short time cannot be explained only considering genetic factors. In fact, not all genetically susceptible subjects develop T1D, and the concordance rate among monozygotic twins ranges from 13% to 68%, being also much more lower in siblings (6%).

Thus, although poorly explored, environmental factors could have a relevant role in the onset of this chronic autoimmune disease, also due to environment-induced epigenetic modulation of gene expression.

The in utero life is particularly vulnerable to the exposure to environmental chemicals crossing the placental barrier, which can produce direct damages in the developing tissues of the fetus, but are also able to modulate gene expression, programming health later in life and late appearance of disease. The onset of T1D, in particular, has been linked with typical epigenetic mechanisms as DNA methylation, histone post-translational modifications, and microRNA dysregulation (Di Ciaula 2016).

Exposure to EDCs can affect the developing immune system, predisposing to immune disease and autoimmunity, and could be associated with the development of T1D secondary to a damage to pancreatic beta-cell (Di Ciaula and Portincasa 2014), to altered immune cell functions, and immunomodulation (Nowak et al. 2019).

Maternal exposure to elevated air levels of ozone during the second trimester, and of NOx during the third trimester of pregnancy, has been linked to occurrence of T1D in offspring (Malmqvist et al. 2015).

The incidence of T1D has been also linked with the exposure to PM10 (Di Ciaula 2016), and possible relationships have been suggested for several other pollutants as sulfates, nitrates, nitrites, N-nitroso compounds, POPs, heavy metals, volatile organic compounds, although these indications require additional confirmation.

Furthermore, animal studies showed that BPA can disrupt calcium homeostasis in pancreatic β cells (Ahn et al. 2018), and can accelerate the development of T1D in nonobese diabetic mice, probably through systemic immune alterations (Bodin et al. 2015) and age- and sex-dependent proinflammatory changes in gut microbiota (Xu et al. 2019). The evidences accumulated so far pave the way to further research protocols.

Thyroid Diseases

Thyroid diseases can depend on both genetic and environmental factors, and, according to available data, exposure to EDCs could have a key role, in particular during the perinatal period.

The thyroid gland is very sensitive to a number of EDCs through different mechanisms, and iodine deprivation could amplify their effects.

The available evidences should not be underestimated in consideration of the major role of thyroid hormones during the development (including neurocognitive development), of the chronic (life-long) effects of thyroid dysfunction, and of the large and increasing burden of clinically evident or undiagnosed thyroid disease in both adult and pediatric age.

As shown by observations in animals, a large list of human-made chemicals diffused in the environment can disrupt thyroid functions through a reduction in thyroid hormone levels, a modulation of the expression of genes regulated by thyroid hormones, and/or by a direct interference with thyroid hormone receptors.

Widely diffused environmental pollutants such as perchlorate (used in rocket propellent, airbag manufacture, fertilizers, food packaging), thiocyanate (smoking, industrial pollution), and nitrate (water and vegetables contaminated by fertilizers, cured meats) can affect thyroid function due to a competitive inhibition of the sodium/iodine symporter (NIS).

PCBs, polybrominated diphenylethers (PBDEs), BPA, phtalates, and triclosan could reduce thyroid hormone levels or act on their receptors.

A number of human studies performed in adults and in pediatric subjects describe a relationship between the body burden of PCB, altered T3 and T4 serum levels, and increased, unchanged, or reduced levels of TSH.

The exposure to PCB seems to be particularly critical during pregnancy, and data from a large European mother-child cohort showed that children in the third exposure quartile for PCB-153 and dichlorodiphenyldichloroethylene (p,p′-DDE) had a 12–15% lower TSH at birth (de Cock et al. 2017).

In a group of 56 children differently exposed in utero to PCBs and dioxins (PCDD/F), high prenatal exposure to these toxics was associated with increased T3, T4, and thyroxine-binding globulin at the age of 8 years (Su et al. 2015).

Of note, besides the effects on hormone levels, not all PCB congeners have similar effects on thyroid function, mainly due to their different effects on thyroid receptors. Results from a study assessing the ability to interact with the thyroid receptors of 209 PCB congeners showed that higher chlorinated PCBs (81 congeners) tend to have antagonistic activity and, conversely, lower chlorinated PBCs (38 congeners) act as agonists (Bai et al. 2018).

Work activities of electronic waste recycling are linked with exposure to PBDEs and PCBs, and relationships between elevated T3–T4 levels and lower brominated BDEs have been detected in workers operating in this field. In these subjects, some PCBs, hydroxylated PCB congeners and highly brominated PBDE congeners were able to influence the expression of genes physiologically regulated by thyroid hormones, thus interfering with hormonal signaling and/or mimicking thyroid hormone effects, and leading to altered gene expression (Zheng et al. 2017).

The chemical structure of penta-brominated diphenyl ethers (pentaBDEs), a flame retardant able to cross the placenta during pregnancy, is similar to thyroid hormones. Data from the Columbia Center for Children’s Environmental Health Mothers and Newborns Study, a prospective birth cohort of African American and Dominican maternal-child pairs showed lower TSH levels in children with the highest exposure to BDE-47 (the main pentaBDE congener detected in humans) during in utero life (Cowell et al. 2019). Early (prenatal) exposure to PBDE has also been associated, in human and animal studies, with altered neurodevelopment, probably by pathogenic mechanisms linked with perturbation in thyroid function (Gibson et al. 2018).

BPA has a chemical structure similar to thyroid hormones and is able to competitively bind hormonal receptors. Due to the ability to affect thyroid hormone signaling, BPA is therefore able to disrupt gene transcription mediated by thyroid hormones and to alter the thyroid hormone-dependent postembryonic development in vertebrates.

Although BPA has been banned in several products, available evidences in vitro and in vivo suggest that also its substitutes, the widely diffused analogues bisphenol S (BPS) and F (BPF), could interfere with thyroid hormone signaling pathways (including those involved in gene expression). In this context, thyroid hormone signaling is activated in the absence of T3. BPS and BPF might also display agonistic or antagonistic effects in the presence of thyroid hormones (Zhang et al. 2018).

Phtalates (in particular diethylhexyl phthalate, DEHP) are able to interfere with the hypothalamic-pituitary-thyroid axis, mainly promoting disrupting effects through altered thyroid hormone synthesis, transport, and metabolism. DEHP, in fact, is able to reduce the expression of the sodium iodine symporter (NIS), to decrease the level of the hormone-binding protein transthyretin, and to increase levels of deiodinase 1 and UDP glucuronosyltransferase (UGT) in the liver. In men, serum levels of free T4 and total T3 have been negatively associated with urinary concentration of monoethylhexyl phthalate (MEHP), one of the metabolites of DEHP, and DEHP has been linked with altered thyroid function in several epidemiologic studies. A recent meta-analysis considering a total of 12,674 patients has shown that exposure to DEHP is able to decrease total T4, and to increase TSH levels, with relevant clinical effects in both children and adults (Kim et al. 2019).

The antimicrobial agent triclosan is able to alter thyroid homeostasis mainly through upregulation of thyroid hormone sulfation and glucuronidation, with subsequent increased thyroid hormone excretion and altered serum hormone levels, mainly in terms of reduced thyroxine concentrations. A prospective, cross-sectional study in 317 women enrolled in the EARTH study showed an inverse association between urinary triclosan concentration and free T3, thyroperoxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) serum levels, suggesting the possibility of concomitant autoimmunity effects (Skarha et al. 2019).

Results from the Agricultural Health Study (a large cohort of male and female pesticide applicators followed over 20 years) confirmed a significantly increased risk of hypothyroidism in ever- as compared with never-use of organochlorine (aldrin, heptachlor, lindane, chlordane) or organophosphate pesticides (coumaphos, diazinon, dichlorvos, malathion), and three widely diffused herbicides (icamba, glyphosate, and 2,4-D) (Shrestha et al. 2018).

The pesticide dichlorodiphenyltrichloroethane (DDT) can decrease the capacity to concentrate iodine, leading to thyroid toxicity. Organochlorine pesticides, due to a structure similar to T3 and T4, mimic thyroid hormones by binding their receptor and causing thyroid dysfunction. They are also able, as dioxins, to activate hepatic enzymes, decreasing serum T4 half-life.

Of note, exposure to pesticides during pregnancy is able to affect the homeostasis of thyroid function in newborns, with possible negative developmental effects.

In particular, in utero exposure to organochlorine pesticides (cord plasma measurements) has been correlated with lower FT4 levels and increased TSH levels (Luo et al. 2017).

In an animal study, the ingestion of a glyphosate-based herbicide by pregnant rats and during 5 days (offspring) after birth was able to disrupt the hypothalamic-pituitary-thyroid axis in male offspring, with decreased concentrations of TSH and altered expression of hypothalamic, pituitary, liver, and heart genes involved in thyroid hormone metabolism and transport (de Souza et al. 2017).

In humans cells, co-formulants present in glyphosate-based herbicides have shown potent endocrine-disrupting effects decreasing the activity of aromatase, a key enzyme regulating the homeostasis of sex hormones, at concentrations 800 times lower than that employed in agricultural dilutions (Defarge et al. 2016).

Exposure to perfluoroalkyl substances (PFASs) has been linked (positive association) with TSH levels and with reduced T4 levels, and might exacerbate hormone alteration during pregnancy, with potential negative effects on the fetus (Calsolaro et al. 2017).

A large study in the US population described a link between altered TSH, T3 and T4 levels, and blood/urinary concentration of heavy metals (mercury, cadmium, thallium, barium, cesium, tungsten) (Yorita Christensen 2013).

Besides the effect of EDCs introduced by dermal contact or ingestion, air pollutants could also have a role in disrupting thyroid function. Results from a large USA cohort exploring pregnancy and birth data in 2050 participants (Children’s Health Study) linked prenatal monthly averages of PM10 and PM2.5 air concentrations with altered thyroid function (increased total thyroxine levels) in newborns (Howe et al. 2018).

Reproductive Abnormalities

A large number of experimental, animal, and human studies point to relationships between exposure to EDCs (mainly pesticides, herbicides, BPA, phthalates, heavy metals, dioxins, PCBs, polybrominated biphenils) and possible adverse outcomes in the reproductive functions of both male and female sex. The effect is mainly due to the estrogenic, anti-estrogenic, or anti-androgenic effects EDCs and to epigenetic mechanisms modulating individual susceptibility to disease occurrence and delayed effects of in utero and/or perinatal exposure, with possible transgenerational effects.

An increasing number of evidences also indicate that air pollutants (i.e., gaseous pollutants, particulate matter, polycyclic aromatic hydrocarbons, heavy metals) are able to affect gametogenesis and to impair reproductive function in exposed populations, mainly acting through endocrine-disrupting activities (estrogenic, anti-estrogenic and anti-androgenic effects), but also as a consequence of increased oxidative stress.

In females, results from animal studies show that early exposure to EDCs can induce negative effects on the developing ovary, acting through epigenetic mechanisms (i.e., altered DNA methylation), on primordial germ cells, gonadal differentiation, folliculogenesis, and ovulation (Zama and Uzumcu 2010).

Several epidemiologic studies depicted robust relationships between organochlorine pesticides (occupational exposure or nutritional intake) and reduced female fertility.

The organochlorine pesticide methoxychlor, in particular, presents estrogenic properties and, as shown by animal studies, its metabolites could act with estrogenic, anti-estrogenic, or anti-androgenic effects, with clinical outcomes also evident into adulthood, following early exposure (Zama and Uzumcu 2010).

Results from animal studies show that ingestion of the herbicide glyphosate can produce several negative effects on pregnant mice, including ovarian failure, altered steroidogenesis-related gene expression and subsequent hormone secretion, oxidative stress (Ren et al. 2018). In rats, postnatal administration of glyphosate generates endocrine-disrupting effects in the male mammary gland (altered development) (Altamirano et al. 2018), and in cattle, may impair reproductive function through altered steroidogenesis and proliferation of granulosa cells (Perego et al. 2017).

Of note, a recent animal study found that glyphosate-induced alterations could be present in future (F2-F3) generations following maternal exposure, and in the absence of a direct exposure of offspring (F3). In fact, a transient exposure of gestating female rats (from day 8 to day 14 of gestation) to a low dose of glyphosate (half of the NOAEL) promoted ovarian disease (polycystic ovaries with negligible granulosa cells) in the F2 (grand-offspring) and F3 (great-grand-offspring) generation glyphosate lineage females, as compared to the control lineage. A delayed pubertal onset was also noticed in males in the F1 and F2 generation glyphosate lineage. In male animals, severe testis alterations (i.e., azoospermia, atretic seminiferous tubules, presence of vacuoles in basal regions of the seminiferous tubules, sloughed germ cell in the lumen of tubules, and lack of tubule lumen) were also recorded in the F2 generation glyphosate lineage, and altered prostate histology (atrophic or hyperplastic glandular epithelium, presence of vacuole spaces in the epithelium) was evident in the F3 generation glyphosate lineage males (threefold increase in disease rate over controls). According to experimental results, these alterations mainly derive from altered germline DNA methylation, an epigenetic alteration (epimutation) with transgenerational transmission, present in the F1, F2, and F3 generation sperm (Kubsad et al. 2019).

The negative effects on female reproductive function of BPA are particularly critical in the case of perinatal exposure. In animals, also after exposure at low doses, BPA can disrupt ovarian morphology and promotes altered timing of puberty, altered oogenesis, altered estrous cycle and LH levels, cystic endometrial hyperplasia, uterine adenomyosis, leiomyomas, atypical hyperplasia and stromal polyps, paraovarian cysts, proliferative lesions of the oviduct and cystic mesonephritic duct remnants (Zama and Uzumcu 2010).

In humans, epidemiological studies showed that infertile women could have higher serum levels of BPA, as compared with fertile females. An inverse association has been indicated, in women undergoing in vitro fertilization, between BPA levels and peak estradiol levels, number of oocytes retrieved, oocyte maturation, fertilization rates, and embryo quality, leading to a decrease success rate of treatments. Elevated urinary BPA levels have also been linked with altered implantation of the blastocyst to the uterine wall, with alterations in the ovarian volume and mature follicle counts, with altered levels of gonadotrophic hormones (Ziv-Gal and Flaws 2016).

Exposure to BPA has also a major role in the onset of polycystic ovary syndrome (PCOS), since higher BPA levels are present in PCOS patients, as compared with controls, being involved in insulin resistance and hyperandrogenism (Hu et al. 2018).

Emerging evidences point to adverse effects on female reproductive function also in the case of Bisphenol S (BPS), widely used as a substitute for BPA. These negative effects should act on folliculogenesis and oocyte quality after long-term exposure to very low doses of BPS (Nevoral et al. 2018).

Exposure to PCBs (either through ingestion or inhalation) could have a significant impact on female reproductive function, affecting the ovarian cycle and potentially disturbing fertility. In a group of naturally cycling women (21–38 years of age), it has been shown that increased levels of estrogenic PCBs were linked to high risk of increased FSH:LH ratio, a marker of reduced ovarian responsivity (Gallo et al. 2018).

EDCs have also been associated with the onset of endometriosis, with significant risk increment linked with exposure to PCBs, organochlorine pesticides, phthalate esters (in particular DEHP), or PFOA.

In males, exposure to EDCs (mainly phthalates, pesticides, herbicides, PBDEs, PCBs) has been linked to low serum testosterone levels and anti-androgen effects, with clinical effects including cryptorchidism, testicular hypotrophy/dysgenesis, and altered spermatogenesis.

BPA, alkylphenols, organochlorine pesticides, and PCBs might have agonistic effects on estrogen receptors, also altering estrogen-responsive gene expression.

The pesticides methoxychlor, DDT, fungicides, and BPA can act as anti-androgen chemicals through androgen receptor antagonism, inhibition of steroid synthesis, disruption of signaling pathways linking hormones with androgen-sensitive tissues, and altered expression of androgen-responsive genes.

BPA, PCBs, phthalates (in particular DEHP), and methoxychlor, also at low concentrations, are able to alter the pathways regulating the biosynthesis of steroid hormones.

In rat, oral exposure to the herbicide glyphosate altered the levels of reproductive hormones, induced oxidative stress, induced significant reductions in sperm count and motility, and increased abnormal sperm cells. These alterations were paralleled by severe histologic testicular alterations (Owagboriaye et al. 2017).

Finally, a number of environmental pollutants (including electromagnetic fields) act promoting oxidative stress through the generation of reactive oxygen species (ROS), with damaging effects on tissues and on sperm count, morphology, and activity (Sidorkiewicz et al. 2017).

Of note, the timing of exposure is a critical factor, since the exposure can start very early (in utero life) with significant and long-lasting effects.

Endocrine Disruptors and Cancer

According to data from World Health Organization, global rates of endocrine-related cancers (breast, endometrial, ovarian, prostate, testicular, and thyroid) have been increasing over the last 4–5 decades and, due to these rapid temporal variations, this trend cannot be explained by genetic factors.

Hormones are strongly involved in the onset and progression of these cancers and, as a consequence, chronic exposure to EDCs can certainly contribute to carcinogenic risk and to the rising cancer incidence.

Breast cancer is the most common cancer among women. EDCs have a role in the early onset of breast development in young girls worldwide, and this effect, in turn, increases the risk for breast cancer. Furthermore, exposures to pesticides, phthalates, bisphenols, or parabens have been linked with incident breast cancer and with possible cancer progression.

It has been shown that some EDCs (p,p′-DDT, methoxychlor, benzophenone-2, bisphenol A, bisphenol S, 4-phenylphenol, or n-butylparaben) are able to upregulate aromatase mRNA, increase aromatase activity, aromatase-induced biosynthesis of the breast carcinogen 17β-estradiol, and increase ERα-positive breast cell proliferation, potentially promoting estrogen-sensitive breast cancer proliferation (Williams and Darbre 2019).

Exposures to pesticides (Lerro et al. 2019), alkylphenols, PCBs, or inorganic arsenic (Gore et al. 2015) have been suggested to be risk factors for prostate cancer.

The risk of thyroid cancer is increased in workers exposed to pesticides (in particular, atrazine and malathion) (Lerro et al. 2019).

Data from the European Epilymph study (2457 controls and 2178 incident lymphoma cases) showed, in men but not in women, a 24% increased risk of mature B-cell neoplasm following over 30 years of occupational exposure to EDCs (Costas et al. 2015). In particular, a number of experimental studies, animal studies, and epidemiologic reports document relationships between exposure to pesticides, non-Hodgkin lymphoma, and leukemia.

Incidence of testicular germ cell cancer is progressively increased over the past 50 years in the majority of industrialized countries, being the most common cancer in the age range 20–45 years. Also in this case, the rapid increase in cancer incidence cannot be explained on a genetic basis, suggesting a major role for environmental factors.

In particular, exposure to PCBs or pesticides (in particular organochlorine insecticides) has been linked with testicular cancer.

Increasing evidences also point to a relationship between EDCs and ovarian cancer, also due to epigenetic alterations mediated by endocrine disruptors.

On the other hand, EDCs have a clear role in the onset and progression of obesity and insulin resistance, well-known risk factors for cancer onset and progression in several districts (i.e., endometrium, esophagus, kidney, pancreas, liver, gastric cardia, colon, breast, ovary, gallbladder, thyroid). It has been calculated that, worldwide, the burden of cancer attributable to obesity (population attributable fraction) is 11.9% in men and 13.1% in women (Avgerinos et al. 2019).

In vitro and animal studies also suggest that early (i.e., in utero) exposure to EDCs, such as PCBs, BPA, phthalates, pesticides, could contribute to cancer onset later in life and epidemiological studies are confirming this possibility.

Fetal exposure to carcinogens introduced by mother with contaminated food (dioxins, PCBs, acrylamide, PAHs) can induce altered genomic expression in newborns (in particular, effects on cell cycle, apoptosis, and immune system), and activation of mediators involved in chronic inflammation and cancerogenesis, all molecular events increasing the risk of cancer in offspring.

A recent survey exploring the use of personal care product use during pregnancy among 527 mothers of patients with testicular germ cell tumors and 562 mothers of controls showed an increased risk of cancer in case of maternal use of face lotion more than one time per week (Ghazarian et al. 2018).

An increased risk of testicular germ cell tumors in offspring has been also associated with maternal prenatal exposure to aromatic hydrocarbon solvents (Le Cornet et al. 2017).

Increased cancer risk during childhood has been indicated following parental pesticide exposure. Results from the Childhood Leukemia International Consortium (pooled exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls) showed a significantly increased risk of acute myeloid leukemia in the offspring after maternal exposure to pesticides during pregnancy, and a slight increase of acute lymphoblastic leukemia after paternal exposure around conception (Bailey et al. 2014).

A meta-analysis on 15 published epidemiological studies exploring the relationships between parental exposure to pesticides and brain tumors during childhood showed that both preconception (father) and pregnancy (mother) exposure may increase the risk of brain cancer in offspring, suggesting that preconception paternal exposure may be as important as maternal exposure during pregnancy (Kunkle et al. 2014).

Endocrine Effects of Radiofrequency Electromagnetic Fields

Preliminary, growing, and, in some cases, convincing evidences indicate possible relationships between the exposure to artificial radiofrequency electromagnetic fields (RF-EMF), a nonchemical, rapidly emerging, and widely diffused environmental pollutant, and several endocrine alterations.

The exposure to RF-EMF (nonionizing portion of the electromagnetic spectrum with frequency ranging from 300 MHz to 300 GHz) is progressively rising, mainly due to the continuous development of sources as mobile phones, radio base stations and receivers, radar, personal computers, tablets and wireless devices, industrial devices, and the forthcoming “Internet of Things” (IoT) linked to 5G networks.

Although, in the majority of cases, the current regulatory limits are respected, a growing number of evidences generate concern about safety also in the case of exposure to low intensity RF-EMF, and the real health impact of this widely diffused form of environmental pollution is still under evaluation.

Exposure to RF-EMF generates local thermal effects (heating of tissues close to the penetration depth of radiation) as a consequence of energy transfer from the EMF source to oscillating charges inside the tissues. This physical effect is generally followed by physiological mechanisms of heath dispersion with minimal health risks. On the other hand, however, exposure to RF-EMF also generates a number of well-studied and hazardous nonthermal, biological, and biochemical alterations with both local and systemic effects.

Of note, the international reference levels for RF-EMF exposure indicated by the International Commission on Non-Ionizing Radiation Protection (ICNIRP, 41 V/m for 900 MHz, 58 V/m for 1800 MHz and 61 V/m for 2100 MHz) are based on the appearance of acute thermal effects, not considering evidences regarding a number of nonthermal biological effects following chronic exposure. Prevention of RF-EMF-induced tissue heating is thus ineffective in avoiding biological and biochemical interferences in human brain, electrical brain activity, immune system, reproductive system, metabolism, oxidative homeostasis, modulation of DNA damage, cancer onset and progression (Di Ciaula 2018).

According to available evidences deriving from animal and human studies, the male reproductive function and, in particular, the testis (due to development and maturation processes of sperm) is highly sensitive to RF-EMF exposure.

A number of evidences indicate the possibility of negative effects of RF-EMF on sperm (i.e., decreased sperm count, altered sperm motility, altered viability, and morphology) and, in turn, on male fertility.

In animals, the exposure to RF-EMF is also able to damage the seminiferous tubules and to reduce the number of Leydig cells resulting in reduced serum testosterone levels and harmful effects of fertility. Oxidative stress induced by RF-EMF exposure (i.e., increased ROS production) is able to generate DNA damage, accelerating sperm cell death and possibly promoting testicular cancerogenesis (Kesari et al. 2018).

Additionally, several studies describe relationships between RF-EMF exposure, shrinkage of testicular size, and, in females, disrupted ovarian cycle, also following prenatal exposure.

Preliminary observations indicate possible effects of RF-EMF exposure on glucose and lipid metabolism. Higher levels of glycated hemoglobin were measured in children exposed to high (9.601 nW/cm2 at frequency of 925 MHz), as compared to those exposed to low (1.909 nW/cm2), RF-EMF generated by mobile phone base stations during 6 h daily, 5 days in a week (Meo et al. 2015).

Additionally, animal studies described a significant rise in serum glucose and insulin levels and an increment in insulin resistance (HOMA-IR) following exposure to RF-EMF from mobile phone (Meo and Al Rubeaan 2013), and histological damages in the liver and in the pancreas (i.e., in the islet of Langerhans) proportional with the duration of the exposure (Mortazavi et al. 2016).

According to preliminary evidences in animals, also thyroid function could be affected by RF-EMF. In rats exposed to RF-EMF at 900 MHz (30 min/day, for 5 days/week for 4 weeks), lower TSH, T3, and T4 serum levels were detected, as compared to the sham-exposed group of animals (Koyu et al. 2005).

Exposure to a 900-MHz pulse-modulated EMF at a specific absorption rate (SAR) of 1.35 Watt/Kg (source similar to that from GSM mobile phones) for 20 min/day for 3 weeks has been able, in Wistar rats, to induce thyroidal hypothrophy and to inhibit thyroid hormone secretion. RF-EMF exposure was also able to enhance caspase-dependent pathways of apoptosis in thyroid cells (Esmekaya et al. 2010).

In humans, a long-term (6 years) study on the effects on hormone profile in subjects differently exposed (in terms of distance from transmitters) to radio frequency radiation emitted from mobiles or base stations showed significant outcomes on pituitary-adrenal axis, with a reduction of ACTH, cortisol, thyroid hormones, prolactin in young females, and testosterone levels in males (Eskander et al. 2012).

Whereas evidences linking exposure to RF-EMF are still scarce, preliminary or controversial, available results should not be underestimated (Di Ciaula 2018). There are demonstrations of biological effects even in the case of levels below the regulatory limits. This is a scenario induced by the wide and rapidly growing environmental exposure, due to the increased susceptibility in pediatric age and to possible interactions with other EDCs.

Summary and Future Trends

The release of large amount of hazardous chemicals in the environment and its worldwide increasing trend have generated an ubiquitous exposure to EDCs and relevant health effects in adults and in pediatric age, as documented by a number of experimental, animal, human, and epidemiological studies.

Exposure to EDCs produces combined effects on multiple districts and could involve all vital functions of the organism (from cell cycle to complex systemic homeostatic mechanisms). The hits may start from early developmental processes and acting through the impairment of multiple endocrine axes. Particular concerns derive from the possibility of having relevant health effects after chronic exposure also at low doses (and/or with nonmonotonic dose-response effects), from the high vulnerability during in utero life and childhood, from the possibility of altered development of multiple organs, and for the capacity to promote late-onset diseases following early exposure.

The causal role of EDCs in diseases with growing incidence (obesity, type 2 and type 1 diabetes, thyroid disorders, reproductive abnormalities, cancer), although evident, needs to be further investigated mainly in terms of effects of combined exposures to multiple EDCs, variable individual susceptibility, epigenetic modulation of gene expression, and transgenerational effects, including cancer risk.

Results from adequate biomonitoring procedures and future experimental and epidemiologic studies will contribute to a better understanding of the complex mechanisms of action of the EDCs and, in the same time, should ameliorate the appropriateness of current regulatory limits, should provide adequate tools for primary prevention strategies, and certainly will contribute to stop and/or reverse the epidemic growth of noncommunicable diseases and cancer, also reducing the high health costs deriving from the exposure to EDCs worldwide.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Internal MedicineHospital of Bisceglie (BAT), ASL BATBisceglieItaly
  2. 2.International Society of Doctors for Environment – ISDEBaselSwitzerland
  3. 3.Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolBariItaly

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