Keywords

10.1 Introduction

The group of molecules identified as endocrine disruptors (EDCs) is highly heterogeneous and includes synthetic chemicals used as industrial solvents/lubricants and their by-products, such as plastic compounds, plasticizers, pesticides, pharmaceutical agents, heavy metals, phthalates, bisphenol A, flame retardants, alkyl phenols, dioxins and polycyclic aromatic hydrocarbons have been identified as endocrine disruptors [1]. Currently, an endocrine disruptor (ED) assessment list is available at the European Chemicals Agency (ECHA) and includes chemicals undergoing an ED assessment under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) or the Biocidal Products Regulation. These substances are listed on the ECHA website updated on 29 April 2022 for discussion to ECHA’s ED expert group [2].

Endocrine disruptor, term first introduced in 1991 [3], is defined as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of endogenous hormone action” [4, 5]. These chemicals can bind to the body’s endocrine receptors to activate, block or alter natural hormone synthesis and degradation, which occur through a plethora of mechanisms resulting in “false” lack or abnormal hormonal signals that can increase or inhibit normal endocrine function [6]. These chemicals are also classified as emerging pollutants because they can be detected in the order of nanograms to micrograms (ng/L and μg/L) using gas chromatography with mass spectroscopy and high-performance liquid chromatography with mass spectroscopy; other methods, like enzyme-linked immune-sorbent assay, emergent new biological methods through biosensors, are also currently widely used [7]. EDCs group can be derivate from anthropogenic activities (synthetic endocrine disruptors) and from natural origins (natural endocrine disruptors [7]. An example of this classification of some EDCs is shown in Fig. 10.1.

Fig. 10.1
Chemical structures. Synthetic endocrine disruptors include, Dioxins, Bisphenol A, 17R-ethinylestradiol, Coplanar polychlorinated biphenyls P C Bs, Parabens hydroxybenzoate P C Bs, Atrazine, and Alkylphenol ethoxylate. Natural endocrine disruptors include estrone, testosterone, 17 sitosterol, 17 estradiol, daidzeine, and estriol.

Structure of common synthetic and natural endocrine disruptors

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In April 2016, the German Federal Institute for Risk Assessment (BfR) reached a consensus about the development of EDCs criteria in relevant EU legislation during a meeting [8]. Data from ecological studies, animal models, clinical observations in humans and epidemiological studies agree to consider endocrine-disrupting chemicals (EDCs) as a significant for wildlife and human health [9, 10].

EDCs are widespread in the environment, and the increase of non-communicable diseases (NCDs), such as cancer, diabetes, obesity, cognition deficit and neurodegenerative diseases, endometriosis, polycystic ovarian syndrome, early puberty, thyroid dysfunction, heart diseases and infertility, has all been linked to these substances exposure with costs in the hundreds of billions of Euros per year [11]. In particular, the exponential increase of cancer and metabolic disease, as well as obesity and diabetes worldwide, correlates with the widespread use of these substances and the costs in relation to morbidity and mortality are enormous [12,13,14,15,16,17,18,19,20,21,22,23].

The scientific research in the last three decades has solidified the knowledge of these chemicals and have been known the transgenerational effects through uterine exposure, for disease [24, 25].

However, the perturbative effects of EDCs on endogenous hormones, historically, have been focused on the reproductive system. In fact, already for some pesticides (thiocarbamates, chlororganics, imidazoles, triazoles and triazines), which determine an antiandrogenic action highlighted by the macroscopic sexual changes found in aquatic animals (particularly because of exposure to herbicides and fungicides) such as the demascolinization in rats and fish [26] and the production of estrogens and hermaphroditism in frogs [27] and other developmental disorder of the male gonad in alligators [28]. Certainly, the largest group of these substances accumulates in tissues and in the environment [29,30,31,32].

These substances cause an antiandrogenic effect in humans too, but they also mimic the estrogenic action, confirmed by both experiments in vivo and in vitro [33,34,35,36,37,38,39,40,41].

The great attention to the reproductive system underlines how it can represent a sentinel organ to environmental stresses, and the epidemiological and clinical data available today, in particular on male infertility, seem to confirm this sensitivity.

There is evidence that semen quality has declined in the last decades, and the incidence of male infertility has increased steadily in many countries [42,43,44]. An important decreasing trend has already been described for sperm concentration from 113 × 106/mL in 1940 to 66 × 106 in 1990 [45] and the same for testosterone levels [46, 47]. According to Levine, total sperm count had fallen by 59.3%/escalate between 1971 and 2011 in Europe, North America, Australia and New Zealand and sperm concentration/mL fell by 52.4% [48]. Other sperm decline is has reported also in China from 2001 to 2015 [49] in Africa, India, Brasil and Iran [50]. Changes in sperm production, initially thought to be due to maternal exposure to environmental oestrogens, corresponds precisely to the introduction of chemicals especially after 1940 [51], but with the most knowledge on experimental data, these effects seem to be due to different types of endocrine-disrupting chemicals (EDCs) [52, 53].

EDCs are now ubiquitous in the environment and their effects do not end with the exposed individual but are transmitted to future generation trough epigenetic changes to the germline, as reported in several studies [54,55,56,57,58,59,60,61,62,63].

However, if changes in behavioural factors and lifestyles, including the introduction and rapid growth of cell phones’ use, the large increase in the consumption of opiates and marijuana, the increase in the consumption of cigarettes and increasing physical inactivity, may have potentially induced alterations in seminal parameters and thus reduce male fertility [64], environmental and chemical contaminants in the workplace are recognized as major risk factors especially for male infertility in both epidemiological and experimental studies [65,66,67,68,69,70].

The incidence of genitourinary tract malformations and reduced sperm quality is indeed higher in people living in areas with a high rate of pollution or in individuals exposed to EDCs for professional reasons. More strikingly, especially in industrialized countries, the reduction of semen quality and/or semen count present differences in areas in the same country or even in the same region, supporting the idea that environmental factors, present in some areas but not in others, may be responsible for the decline in semen quality and sperm count [71,72,73,74,75,76,77,78,79,80,81,82,83,84]. Furthermore, different studies have reported that in high environmental pressure areas there is an increase of infertility, urogenital malformation and chronic disease (cancer, diabetes, etc.) [11, 77,78,79,80,81,82,83,84,85,86,87,88].

These epidemiological data are important to understand the shared biological mechanisms mediated by contaminants. There are therefore several evidences that show how ubiquitous presence of chemicals in the environment and in food is actually the root cause of increased health reproductive problems, especially for the reduction of semen quality, and the increased incidence in recent years, even of testicular dyskinesias, induce to believe that harmful environmental factors can have a much more important role than people think.

However, for ethical reasons, it is difficult to establish a causal relationship on human beings. Clinically, the most common manifestation of contaminants is a reduced sperm concentration, while its most severe form can include an increased risk of testicular cancer [89].

Associating both environmental data and chemical factors of exposure to the data found in the body, as well as verifying the consistency and the determinism or order of passage from the environment to the organism, is a crucial step for a better understanding of the environment-health relationship. In light of this, the male reproductive system is sensitive to a broad variety of environmental pollutants; therefore, it represents an optimal model for the study of environmental health. Spermatogenesis from puberty onward is continuously exposed to insults at the stages of continuous replication; as a consequence the male germline accumulates mutations [90, 91]. Sperm cells are more susceptible than eggs to the effects of oxidative damage, because they lack significant antioxidant protection because of reductive cytoplasmic space for an appropriate armoury of defensive enzymes and significant amounts of polyunsaturated fatty acids [92]. Simultaneously, in semen it is possible to measure environmental contaminants and in vivo effects on sperm cells, which are readily available, with features sensitive to environmental pollutants such as motility, morphology and the integrity of the DNA strand. If human semen seems an earlier and sensitive source of biomarkers than blood in monitoring high environmental pressure on human health, therefore it can be considered a reliable environmental sentinel [77, 78, 93]. More evidence in literature indicates the human semen as an important health marker. In fact the spermatogenesis cycle is extremely complex and vulnerable to endogenous and exogenous stress, so it is not surprising that it can be an important indicator of the state of well-being of the organism. Recent studies have demonstrated the association between semen quality and state of health [94,95,96], correlating the former with chronic degenerative diseases.

As a matter of fact, male infertility is becoming a public health priority, and it’s also related to an increased risk of later onset adult diseases, especially cancer [11, 97,98,99,100,101] not only testicular cancer [102,103,104], medical comorbidity [105], shorter life expectancy [106] and trans-generational effects [107, 108].

In this prospective, fertility assessment, sperm may be an indicator of overall health and the attention on maximum fertility age (18–35 years) can be important for chronic diseases prevention. In addition to the potential preventive and predictive role of reproductive biomarkers for chronic adult degenerative diseases, the growing interest on the transgenerational effects induced by pollution and lifestyles through epigenetic modifications on gametes shifts the interest of prevention as far as preconception; therefore, the interest for the reproductive system and biomarkers assumes a greater significance for safeguarding the health of future communities [107, 109].

However, given that a healthy environment and the mother’s lifestyle are crucial for the offspring’s health, and the utero window represents a field of study of Developmental Origins of Health and Disease (DOHaD) [110, 111], the Paternal Origins of Health and Disease paradigm (POHaD) should be taken into serious consideration [112,113,114,115,116,117,118]. Nevertheless, in spite of having few epidemiological studies on humans, the perspective opening the systematic study of reproductive biomarkers in environmental impact assessment and early and predictive health risk assessment is enormous [107].

Considering both the great impact of EDCs on the environment and health system and the need to protect and reduce their impact, policy implication and community interventions are mandatory. In this sense, the following chapters will point out the most important plan directions of principal public institutions in the frame of more recent knowledge on these contaminants.

10.2 Europe Police Priorities on EDCs: REACH Regulation, European Plant Protection Products Regulation (PPPR), Biocidal Products Regulation (BPR)

In Europe, general future priorities for protecting humans and wildlife from adverse effects of EDCs were reported at the Weybridge meeting in 1996 [119] and later in 1999 [120] a community strategy for EDCs was adopted. This was a fundamental step for addressing a regulatory basis on health and environmental effects caused by EDCs. European policy embraces the precautionary principle aimed at limiting exposure to agents harmful to humans, animals and the environment even in the absence of scientific certainties. The precautionary principle in the rules of the UE gives particular attention in the comparison of the danger of exposure of the fetus in utero and in its subsequent development. The EDC strategy, indeed, was characterized by a series of actions for monitoring programs and estimating exposure and effects of EDCs, to define and check testing methods and other actions for research on EDCs and consequently to develop regulatory actions. All instruments adopted for long-term actions under ED research group of European Union (EU), for example the 7th Environment Action Programs (EAPs) [121] were meant to protect all living species in EU. In 2006, REACH, officially Regulation No. 1907/2006, a regulation of the European Union, dated 18 December 2006, concerning the registration, validation, authorization and restriction of chemical substances [122], defines EDCs as substances of very high concern (SVHCs) for both health and environment, in order to reduce their use and replace them with other safer substances. Before 2007, EDCs had been considered responsible for the development of reproductive problems and cancer lesions, and therefore regulated. Currently, the EDCs risk assessment is specifically applied in the context of chemical classes in use. REACH requires companies to register substances and give data for ensuring safe handling; if the chemical is identified as an SVHC, it is included in a list of restricted chemicals under consideration of REACH for possible authorization. The European Chemicals Agency (ECHA), indeed, evaluates in first instance the chemicals included in the Authorization List for allowing their entry into the market after evaluation on the basis of article 57 of REACH regulation, which refers to the toxicity, carcinogenic bio accumulative, environment persistence properties and possibility to be replaced with safer alternatives.

The European Plant Protection Products Regulation (PPPR) on EDCs [123], although approved after REACH regulation, it was the first (EU) to take into account health effects and non-target organisms, evaluating the substances at mutagenic, carcinogenetic or toxic level on the basis of the regulatory system of classification, labelling and packaging (CLP). Nevertheless, the PPPR does not contain indications to define a substance with endocrine-interfering properties, consequently it referred with amendments to the regulation based on the WHO IPCS regarding the definition of "endocrine disorder" and "adverse health" (Table 10.1) [124]. Two derogations to the PPPR on EDCs were applied, but no agreement has been reached on the handling of these derogations until now (Derogations: 1. the necessity for an active substance to control a serious danger to plant health (Article 4, paragraph 7). 2: negligible exposure towards an active substance, safener or synergist (Annex II, point 3.6.5) [125]

Table 10.1 WHO IPCS definitions
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In 2009, Plant Protection Products Regulation banned EDCs in pesticides and in the 2018 the European Food Safety Authority and European Chemical Agency produce a guideline for identifying EDCs present in pesticides.

The Biocidal Products Regulation (Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products) [126], has been the second European Regulation on substances used in biocidal products and has been applicable since 4 June 2018 (European Commission, Commission Delegated Regulation (EU) 2017/2100 of 4 September 2017 setting out scientific criteria for the determination of endocrine-disrupting properties pursuant to Regulation (EU) No 528/2012 of the European Parliament and Council, 2018) [127]. The most important difference compared to PPPR is that, in case of a substance having endocrine-disrupting properties, the application is approved for 5 years only and a product containing them it cannot be authorized for public use.

For medical and in vitro diagnostics devices, an EU regulation consolidated data on 24 April 2020 (Consolidated text: Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (Text with EEA relevance) [128] and individualized only substances that in contact with the body pass to higher concentrations 0.1% weight by weight and have a justified endocrine interference property. These findings have been reported and discarded. A consolidated text of EU regulation for in vitro diagnostic devices on 28 February 2022 (Consolidated text: Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (Text with EEA relevance) [129], labelling the presence of endocrine interfering properties must be mandatory. For cosmetics, in the 2009 regulation, there are no reported endocrine interfering properties, although the problem was later addressed in 2018 leading to a commitment of the ED commission to define these ED properties and possibly limit or in any case avoid their use. In the light of this, REACH regulation should also address the environmental matter.

In order to release these substances in contact with food, although Regulation (EC) No. 1935/2004 does not generally allow it the release, much is handed over postponed to national laws; however, greater attention is paid to the release of plastic material, which is absolutely not allowed to be used in children’s food; the same level of Bisphenol A release was reduced from 0.6 mg kg−1 food to 0.05 mg kg−1 food (Commission Regulation (EU) No 10/2011 of 14 January 2011, on plastic materials and articles intended to come into contact with food). Bundesinstitut fu¨r Risikobewertung (BfR), Database BfR Recommendations on Food Contact Materials) [130].

The Water Framework Directive (WFD) 2000/60/EC regulate known or suspected EDCs in water. In fact there are substances that are detected and that have already been banned from the market for some time. In 2020, 205 substances were included in the substances of very high concern (SVHC) list, 16 of these substances were included due to their endocrine-disrupting characteristics, currently these are included in a list of 45 chemical substances. Another list of substances including pharmaceuticals are monitored and under evaluation for health and environmental risk substances.

10.3 Other EDCs Regulations

EDCs have been also identified as an emerging policy issue by the UN Environment Programme (UNEP), which oversees global policy through strategic alliance for International Chemical Management. In 2015, the alliance welcomed the 2012 WHO and UNEP State of the Science report on EDCs [131]. In this report, tests exclusively focus on the estrogen, androgen and thyroid pathways [132] and do not take into account neither other receptors nor many other receptors mechanisms of action [133]. In 2017, UNEP identified 28 Policy actions, worldwide characterized by the variability to regulate the use of hazardous EDCs [134].

Currently, the various existing regulations share an agreement to limit a subset of persistent organic pollutants, including many EDCs. At the same time, the USA do not take into account the agreement and continue to market chemicals that the agreement has banned.

10.4 Economic Burden

The Food and Drug Administration has identified more than 1800 chemicals; today, medical societies and governmental agencies are experiencing an increase in health problems created by the action of EDCs and their effect seems to be transgenerational, occurring over at least two or three generations.

Considering nutrition is the main route of exposure to EDCs in human beings, we are currently witnessing a global and massive process of orientation and categorization of food consumption, through customs and lifestyles. This widespread exposure to EDCs and their consequent pathologies are diversified not only by gender characteristics but also by different age groups as well as economic income.

As previously stated, the most common way one comes into contact to EDCs is through food; however, people who work using these chemicals are exposed to them daily. EDCs can have long term and severe adverse effects on unborn babies’ hormone system too, as shown over the last generation. The next generation will experience the same, or worse, if no future regulatory strategy for prevention is adopted. Indeed, the presence of EDCs in the environment and people’s daily habits can expose the unborn child, from the embryonic stage onward, to these chemicals through feta–placental contact with the mother. The severity of the pathologies created range from pathologies of the male and female reproductive systems, to diabetes, cancer and diseases that affect the cognitive system by conditioning the level of IQ [135,136,137,138].

The Global Burden of Disease project uses an approach that calculates disability-adjusted life-year (DALY) [139], thanks to which the costs [140] of intellectual diseases and disabilities are also assessed. Nevertheless, due to its complexity, the DALY system remains insufficient to evaluate the intellectual damage to the human being [141].

Recently, several assessments have been carried out on the costs of diseases and damage caused by exposure to EDCs, such as neurobehavioural defects, disorder of the male and female reproductive systems, obesity and diabetes [135,136,137,138]. The economic burden results in 163 billion euro for EU, and 340 billion dollars for the USA annually, which means that not only this evaluation has been underestimated but also that only a few EDCs and their effects on health have been investigated [142,143,144].

It is therefore clear that a regulation aimed at identifying EDCs facilitates their replacement and prevents exposure by informing the population on how to avoid EDCs.

10.5 Limiting Exposure to EDCs

To give a clear indication for the hoped regulations is to promote the EDCs definition given by Endocrine Society as “any chemical or mixture of chemicals that interferes with any aspect of hormone action” [4]. This definition has the possibility to be applied anywhere globally: in all sectors of the economy and jurisdictions of the world. It also has the clear potential to deeply analyze what the damage is to the general population and to the specific exposed workers. It has the ability to calculate what the costs of treating the diseases are and the inconveniences caused to humankind, surrounding nature and the environment.

Differently, the definition given by WHO specifically requires an adverse effect to be documented [6, 145, 146]. Pointing out an adverse effect to define an EDC is problematic because regulatory agencies often disagree on which outcomes are adverse [147].

Perhaps, the time has come to consider EDCs among global burden diseases; this assessment becomes more evident if we consider the health costs paid by people exposed to EDCs and the costs that are paid by communities to treat the diseases [148].

We are realizing day by day that the population’s exposure to EDCs creates pathologies involving the female and male reproductive system, which reduce their abilities and also, in some minority groups of the population [149], create disabilities, including neurocognitive ones [138].

We should avoid searching with great difficulty the critical levels of tolerability as a risk-based approach assumes [150]. Furthermore, many EDCs can act at low concentrations and often present non-linear dose–responses; these properties represent a regulatory challenge.

Indeed, for several EDCs, it’s not possible to evaluate a safe threshold for the toxicity, especially for neuro developmental deficits. In this regard, in a Danish report, the aim of obtaining an additional and pragmatic choice for the evaluation of safety was discussed [151].

Differently, in a hazard-based approach, once identified the hazardous properties of a chemical, it becomes sufficient to prohibit market use regardless of the exposure and economic cost. It is difficult to imagine that the regulation of an EDC must wait for full-blown pathological effect instead of preventing it. If we consider pathologies such as cancer, diabetes, or all malfunctions of the male and female reproductive apparatus and neurocognitive problems, it becomes very complicated to accept a logic that exposes humans and the surrounding environment to suffer inert the snare of EDCs.

10.6 Policy Management and Recommendations

We need regulatory recommendation of EDCs, pointing on their identification, a policy geared to monitor and reduce exposure to better protect humans and the environmental health.

The first recommendation is on the identification of EDCs. This is the necessary basis for an effective action.

The Endocrine Disruptor Screening and Testing Advisory Committee [152] promotes evaluation of estrogen, androgen and thyroid receptor disruptions.

Despite these clear indications, in the USA, regulation requires testing for estrogen only for few materials in use.

To obtain better EDCs identification, we would probably need more sensitive tests to some EDCs and clarify more pathways for each estrogen, androgen and thyroid receptor.

For thyroid axis, identification disruptors are scarce, and, for many pathways, they are completely absent. Furthermore, we need to modify some test modalities for disruptor identification, which could give misleading results, for example, the changes in uterine weight test under high concentrations of estrogenic EDCs [153, 154]. At the same time, to this day, a whole series of capable tests for a broader number of nuclear receptors, and other receptor types, is available, which is also capable of assessing several mechanisms of action for EDCs [155]. This capable test should be inserted in regulatory requirement after validation. The Organisation for Economic Cooperation and Development guidance provides new assays to test more pathways than those required from EU and USA regulation.

As soon as possible, we need tests to identify EDCs involved in adipocyte development, steroidogenesis and all reproductive functions to begin from spermatogenesis and other female reproductive system pathologies or dysfunctions (e.g. endometriosis, polycystic ovary syndrome).

Human diseases should become the first-tier management to identify EDCs and their adverse impact [156]. The difficulty to recognize the effects induced by EDCs is found in the regulations that encourages just in vivo observation. This means that we need to use vertebrate animals or epidemiological evidence, but the regulatory authorities have proposed strong limitations to use mammals for regulatory testing and at the same time we do not have sufficient in vitro guidelines for this shortcoming. Likewise, the non-mammalian vertebrate and invertebrate models have not the possibility to overcome the shortcoming information.

We need more typical mammalian models (egg rodents) evidence to validate in vitro testing and have the possibility to examine complex effect on health.

All this limitation takes risk of EDCs identification. A determination of adverse effect should be sufficient for identification as an EDC and subsequent regulation.

Obviously, the search for already tested chemical safer substitutes should be supported and developed by different governments. Before chemicals get into the market to be used by the population, they should be tested in vitro and in vivo in order to give a guarantee not to alter the state of human health and the surrounding environment. Unfortunately, some substitutions used up to now for polybrominated diphenyl or BPA remain questionable and dangerous in other pathways. Another recommendation concerns the exposure to EDCs. Once identified, an EDC should be excluded from the possibility of human exposure. A risk-based regulatory approach currently prevails in which the effects are evaluated on the basis of exposure degree. This means that we need a specific monitoring for each single EDC conjugated to each environmental reality, economic development system lifestyle and profession.

It is essential that decision makers know how chemicals are being used.

Information campaigns could be organized for the general population or population particularly exposed to EDCs. An action of this dimension could change exposure levels by informing and raising awareness of how to avoid the possible and different contact with individual EDCs and defend health from the sneaky snare of EDCs.

10.7 Conclusion

EDC policies are justified on economic grounds and to further environmental justice.

The endocrine disruptor is constantly expanding its range of influence on the globe population. We are currently witnessing what’s happening in the surrounding environment.

On the scientific level that works on the identification of chemical substances with altering characteristics of the functional systems of living organisms, it is necessary to expand the possibilities of directly investigating altered processes in vivo on animal models. The hazard-based approach, meant to guide and reach the regulations, should be preferred to the risk-based one.

The health risks are considerable as the social costs associated with poor health conditions are, in this sense, representative signs are emerging both in the number of women and men involved and in the developed dysfunctions.

In particular, since it is better measurable, great evidence of how much human activities are seriously impacting the quality of the planet, and, consequently, of human health, can be precisely deduced from the progressive semen quality decline, which probably represents the impact best. The reproductive system, in particular the male one, can be represented as a “Sentinel Organ System” due to its extreme sensitivity to environmental stress; recent evidence indicates human semen as an early and sensitive source of exposure, therefore a useful tool for measuring the presence and effects of chemical substances not only on the classic seminal parameters (number, motility, morphology and DNA sperm damage) but also on others that are now better studied in vivo with molecular biology techniques. Exposure assessment, in conjunction with information on the inherent toxicity of the chemical (i.e. the expected response at a given level of exposure), plays a key role in predicting the likelihood, nature and magnitude of adverse health effects. The use of reproductive biomarkers for early risk detection represents a possible new methodological approach where they could be exploited as early indicators of environmental toxicity and enhanced risk of chronic adverse effects not only for reproductive health. In particular, human semen as an early and reliable source of biomarkers, giving information on biologically active exposures, can be very useful for preventive health surveillance programs, especially in environmental risk areas. This approach appears very promising, above all, in young people (maximum fertile age:18–35 years), considering the possibility to reduce the chronic-degenerative diseases in future adults. In this context, many scientific findings regard the association between pollution and fertility problems. Therefore, the safeguard of germ cells is a new challenge to reduce the burden of epigenetically transmitted diseases.