Environmental Endocrine-Disrupting Chemical Exposure: Role in Non-Communicable Diseases.

The issue of EDCs is puzzled due to lack of scientific data and many gaps in knowledge, it is still essential to frame regulatory policies to deal with the present scenario. Framing of policies and regulations must go parallel with ongoing research and any measure must be compliant to rapid advances in scientific knowledge. At present countries having regulations addressing the manufacture, use and disposal of various chemicals includes carcinogens, teratogens, mutagens and substances that interrupt reproduction. EDCs represent a relatively new classification, involving diverse chemical classes that are able to mimic endogenous hormones. Although there is no agreement on their regulation, EDCs are addressed in different cases in EU law, such as the Water Framework Directive, Registration, Evaluation and Authorization of Chemicals (REACH), Plant Protection Products Regulation (PPPR) and Cosmetic Regulation ( Table 2 ). The government and regulatory agencies of developing countries with large population and huge plastic consumers may restrict the use of endocrine disrupting chemicals in the production of cosmetics, food-contact plastics, plastic water tanks and packaging materials and may provide guidelines on the use of EDC's/plastics, awareness on its harmful impacts and the use of risk-free alternatives must be provided, with an intention to ensures the safety of vulnerable group such as infants, children and pregnant women. The challenges that arise from the field of endocrine disruption are the immense diversity of chemicals produced, but not tested, the mixtures and the unknown interactions between them, together with their consequent effects. The lack of an effective and strong legislation and regulation poses a significant threat to humans, animals and plants, and contributes to the exposure to chemicals that may disrupt the endocrine system. Regulations on controlling EDCs in various countries.

A large fraction of EDCs acts through oestrogenic and androgenic receptors; therefore, researches have focused on their relation to hormone-dependent cancers. Such neoplasm's include breast, endometrial, ovarian, and cervical cancers in women and prostate cancer in men. The incidence of these cancers has risen at a higher rate over the last few decades ( 187 – 189 ). As other non-communicable disease, this increase is multifactorial, and change in lifestyle, industrialization and EDCs are thought to be responsible at least in part ( 161 ). The development and progression of estrogen-dependent malignancies, particularly breast cancer, depend on prolonged or exaggerated estrogen exposure ( 190 ). Approximately 70% of breast cancers are sensitive to estrogen as they show ER-positivity ( 191 ). Unopposed estrogen or estrogen-mimicking EDCs can bind to ER, switching on the downstream signaling of estrogen-responsive genes involved in the cell cycle ( 64 , 192 , 193 ). Several oestrogenic EDCs, such as BPA and phthalates, have been shown to induce epigenetic modification or genotoxic effects ( 27 , 194 , 195 ), which can alter gene products and genetics, eventually predisposing to certain diseases. However, only a few human studies have explored this association so far. Although meta-analysis did not find any association between organochlorine pesticides and breast cancer ( 196 ), another study linked it to exposure before 14 years of age ( 197 ). A study in Mexico showed a positive correlation between MEP, a phthalate metabolite, and breast cancer while other phthalates (MBP, MEOHP, and mono [3-carboxypropyl]) had negative correlation with breast cancer risk. The evidence of any relation between BPA exposure and breast cancer is weak, and it is observed only in animal studies. This may be due to its short half-life so that measurement of exposure is difficult ( 161 ). Agricultural Health Study, USA, has found that several pesticides are linked with increased risk of prostate cancer ( 198 , 199 ). The link between EDCs and other hormone-dependent cancers is tenuous as it is based on a handful of animal and laboratory studies. It has not yet been explored through human studies, and it constitutes a lacuna in our knowledge.

Prenatal exposure to EDCs is thought to affect brain development in the fetus, and some neurodevelopmental abnormalities have been attributed to them. Prenatal BPA exposure has been linked to poor social behavior ( 145 , 146 ), higher anxiety and depressive behaviors ( 147 ). Some studies have suggested a sex-specific effect of BPA on behavior. A study showed that poor social behavior was found to be more pronounced in girls ( 146 ), while a study showed that significant positive associations were found between prenatal BPA and emotionally reactive and aggressive behavior in boys ( 148 ). In another study, prenatal BPA exposure was noted to be associated with increased anxiety and depression in boys but not in girls ( 149 ). The gender difference is likely due to the close relation of brain development with gonadal hormones as proven by animal studies. The brain, particularly hypothalamus, has been shown to be affected by oestrogenic EDCs in a sex-, time- and exposure-dependent manner ( 150 ). In utero exposure to phthalates is shown to be associated with adverse cognitive and behavioral outcomes such as lower IQ, attention deficit, hyperactivity and poorer social communication in children ( 151 – 153 ). Other EDCs such as organophosphates ( 152 , 154 ), PBDEs ( 155 , 156 ), perfluorinated compounds ( 157 ), and PCBs ( 153 , 158 ) have also been linked to adverse neurodevelopmental performance, behavioral problems and lower IQ to varying degrees. There is also some evidence that some PBDEs and PCBs affect neuropsychological status in adults ( 159 , 160 ). Animal studies have provided ample evidence that EDCs act on developing brain through multiple mechanisms: (a) steroid hormones and receptors, (b) neuroendocrine system, and (c) epigenetic changes ( 161 ). One of the main biological mechanisms proposed for adverse neurodevelopmental effects of prenatal EDC exposure is disturbance of thyroid hormone homeostasis, which is critical for fetal brain development ( 162 ).

Effects of environmental pollution on human health are increasingly gaining more attention globally. Environmental pollutants are chemicals that result from human activities, which end up in the environment and subsequently pose risks to human and animal health. Several of these chemicals are collectively known as endocrine-disrupting chemicals (EDCs), which are nowadays gaining more importance in terms of public health due to their widespread effects on human health and potential cause of morbidity. The Endocrine Society defines EDCs as follows: “an exogenous (non-natural) chemical, or a mixture of chemicals, that interferes with any aspect of hormone action.” These chemicals alter the hormonal balance of the body through several different mechanisms; they can mimic hormones, disrupt hormone synthesis or breakdown, alter the development of hormone receptors, act as hormone antagonists or alter hormone binding. Environmental EDCs are mostly released during manufacture and use of human-made materials such as pesticides, plastics/plasticisers, electronic wastes, flame-retardants, metals, food additives, and personal care products. These EDCs can disturb hormonal balance and consequently result in several health disorders, including developmental and reproductive abnormalities, increased prevalence of hormone-sensitive cancers, neurodevelopmental delays and abnormal growth patterns in children, and alterations in immune function. EDCs are a group of highly heterogeneous synthetic chemicals used in a variety of settings. Some of the common chemicals included in this group are chemicals used in industries and their by-products (polychlorinated biphenyls [PCBs], polybrominated biphenyls [PBBs] and dioxins), plastics (bisphenol A [BPA]), plasticisers (phthalates) and pesticides (methoxychlor [MXC], chlorpyrifos and dichlorodiphenyltrichloroethane [DDT]). Some EDCs were designed to have long half-lives for industrial purposes and are known as “persistent organic pollutants” (POPs) exemplified by PCBs, dichlorodiphenyldichloroethylene (DDE), dioxin, organochlorine pesticides and hexachlorobenzene (HCB) ( Figure 1 ). The POPs are highly lipophilic and tend to accumulate in the adipose tissue. Due to this property, they also accumulate in the food chain and undergo biomagnification. Many of these substances either do not decay or decay slowly, while others may be metabolized to compounds that are more toxic than the parent chemicals ( 1 , 2 ). Other EDCs such as BPA and phthalates may not be persistent but are used so extensively that environmental exposure is widespread. EDCs are present ubiquitously in the environment and human exposure occurs through intake of water and food, via inhalation, and through the skin. Sources of environmental EDCs and their effects on metabolism. DEP, Diethyl phthalate; DEHP, Diethylhexyl phthalate; DBP, Dibutyl phthalate; PFOS, Perfluorooctanote; DDT, Dichlorodiphenyltrichloro ethane; PBDE, Polybrominated diphenyl ether; TPTO, bis (triphenyltin) oxide; TBT, Tributyltin. Exposure of plastics to high temperature can lead to leaching or migration of toxic components in environment in the form of microplastics or nanoplastic. In drug delivery system micro- and nanoplastic are used via intravenous, oral, and transcutaneous routes ( 3 ), and also there is a migration of nanopolymers from various packaging materials into food ( 4 , 5 ). Microplastics or nanoplastic accumulates in food chains making them bioavailable again for direct or indirect human exposure via ingestion, skin contact and inhalation ( 6 ). Biomonitoring studies have shown that Human consumption of animals that exposed to microplastics and additives persist in human population and can be harmful for human health ( 7 , 8 ). At present health impact assessments that exclusively focus on the plastic compositions of products while overlook the thousands of plastic additives and their effects. Drinking water particularly is thought to be a source of significant exposure through leaching, industrial waste discharge and inadequate treatment of water supply for chemicals. EDCs can also be transferred from mother to child through trans-placental route as well as through breast milk. Developing fetuses and children are highly susceptible to environmental exposures, and their effects may not become apparent until a later age. Research shows that such exposures may increase the susceptibility of the child to several non-communicable diseases in their adult life ( Table 1 ). EDCs can potentially target various hormone systems; however, it has been observed that the effect of these chemicals primarily involves the reproductive system, puberty, embryonic development and sex differentiation in fetal life. Thus, it is likely that the primary mechanism of their action is through interference with sex steroid hormones. Furthermore, there is also a growing apprehension that metabolic disorders of adult hood may be linked with EDCs. Several in vitro, in vivo and epidemiological studies link human-environmental EDC exposures with obesity, metabolic syndrome, type 2 diabetes and possibly with some hormone-responsive cancers ( Figure 2 ). Studies documenting associations between different EDC exposures and risk to different diseases. Health Effect of Endocrine disrupting chemicals. Tributyltin (TBT), PerfluorooctaneSulfonate (PFOS), Perfluorinated compounds (PFCs), Perfluorooctanoic acid (PFOA), Bisphenol A (BPA), Diethylstilbestrol (DES), hexachlorobenzene (HCB), dichlorodiphenyltri-chloroethane (DDT), Polybrominated diphenyls ethers (PBDEs), constitutive androstane receptor (CAR), Thyroid Hormone Receptor (ThR), glucocorticoid receptor (GR), Aryl hydrocarbon receptor (Ahr), Androgen receptor (AR), Peroxisome proliferator-activated receptor (PPAR), Estrogen receptor (ER), Liver X Receptor (LXR). The breadth of this review identifying negative human health impacts of various EDC's strongly suggests that there are significant risks to human health and a precautionary approach and human bio-monitoring of EDC's is warranted.

Chronic kidney disease (CKD) is a worldwide health menace of growing concern, and its prevalence all over world is estimated at 13.4% ( 177 ). Kidneys serve as the filtration unit and thus are exposed to all compounds in a greater degree compared to other organs. Humans are not exposed to a single compound but to mixture of compounds and they are likely to affect the kidneys as well. Without a doubt, many non-persistent EDCs, e.g., phthalates, bisphenols, benzophenones, and parabens, share common exposure sources such as plasticware and personal care products in various things. There are growing evidences suggesting that non-persistent endocrine disrupting chemicals (EDCs), are linked with adverse kidney function ( 178 ). Studies also showed that exposure to di-(2-ethylhexyl) phthalate (DEHP) through the consumption of contaminated milk was associated with micro-albuminuria in children ( 179 , 180 ). The US National Health and Nutrition Examination Survey (NHANES) delineated the association of urinary phthalate metabolites with CKD markers such as albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and urinary protein-to-creatinine ratio (UPCR) has also been revealed in a population of children ( 181 , 182 ). Urinary BPA levels were also associated with ACR among the US children ( 183 ), as well as Chinese adults ( 184 ). Patients on dialysis have more exposure to BPA due to daily use of dialysis tubing. BPA levels are higher in patients undergoing hemodialysis and peritoneal dialysis, than in healthy controls ( 185 ). NHANES 2003–2006 Estimated Glomerular Filtration Rate (eGFR) among a general population of the US adult females shows positive association with urinary BPA levels but not in the adult males ( 186 ).

EDCs do not behave in the manner of usual toxins. Unlike occupational exposure, environmental exposure to ubiquitously present contaminants occurs not only in low doses as discussed earlier, but also simultaneously to a variety of chemicals in varying combinations. Several of these EDCs act through the same receptors either in agonistic or antagonistic mechanisms. The possible combined effects may be additive, synergistic, antagonistic or nullifying ( 237 , 238 ). In combination, it is even possible to affect different from individual chemicals. It has been demonstrated in animal studies that combinations of EDCs can produce effects in levels at which these chemicals do not induce any measurable effects individually ( 237 , 239 ). This unique property of EDCs has been termed as “cocktail effect” by some researchers ( 240 ). The interactions of chemicals in the mixture appear to be dose-dependent, adding to the complexity further. One of the drawbacks of most epidemiological studies and animal studies is that they take into account each chemical one by one. Thus, the results in these studies may not precisely effect reflect the environmental effect. A study evaluating presence of mixtures of organochlorines in the sera of healthy women and women diagnosed with breast cancer found that only dichlorodiphenyldichloroethane (DDD) individually showed a moderate increase in the risk of developing breast cancer. They also found that a combination of aldrin, p,p′-DDE and DDD was more frequently present in breast cancer patients while it is absent in healthy women ( 241 ).

MKumar, MKumawat, SS, and DS: manuscript draft. RT and AP: overall review. VV: manuscript drafting and editing. All authors contributed to the article and approved the submitted version.

To elucidate associations of urinary EDC's like phthalate with blood pressure (BP), a cross-sectional analysis of 6–19 years children in the 2003–2008 National Health and Nutrition Examination Survey (NHANES) was carried out which reveals an increase in blood pressure associated with 3-fold increase in urine phthalate (DEHP) ( 59 ). A study conducted in people living near a dioxin-contaminated area showed that increasing serum dioxin levels are correlated with elevated diastolic blood pressure. In addition, the prevalence of hypertension was also found to be correlated with serum PCDD and PCDF levels in Taiwanese and Florida adults with dioxin exposure ( 60 , 61 ). Similarly, high serum PCB Level was also found to be associated with elevated blood pressure in NHANES 1999–2002 and NHANES 1999–2004 participants ( 62 ). Studies derive conclusions about the effects of EDCs on hypertension but further studies with larger diverse cohorts are now needed to verify an association between EDC's exposure and risk of hypertension.

Climate change has been globally acclaimed as a major environmental risk, also when combined with chemical pollution and habitat loss it has the potential to have a severe impact on human health. The impact of escalating climate change has added exigency to the rising problem of EDC's pollutants. A study by Brown et al. ( 297 ), the first of its kind, showed that climate change could amplify the deleterious effects of pollution from EDCs on aquatic environments. Climate change is influencing the rate at which toxic chemicals are released from plastic materials, stockpiles and polluted sites. Higher temperatures increase the release of persistent organic pollutants (POPs) to air by changing their rate of partitioning between air and soil, and between air, water and sediment. POPs persist in the environment, bioaccumulate through the food chain, and pose a threat of causing detrimental effects to human health ( 298 ). The fate of environmental POPs in these ecosystems is controlled mainly by temperature and biogeochemical processes. Climate change may increase the re-emissions and redistribution of POPs in different environmental settings via soil–air exchange. Soil–air exchange is a main process of controlling distribution of POPs and terrestrial ecosystem carbon at local and universal scales. Each POP has a moving potential in air and/or water and can bioaccumulate in biological system such as lipid-rich tissues and biomagnified through terrestrial and aquatic food chains ( 299 ). Hence, POPs have a potential adverse impact on higher trophic organisms in aquatic as well as environment ( 300 – 302 ) and on human health ( 303 ). Moreover, intensification of global warming, an increase in POPs levels has been reported in different settings of environment because of the release from reservoirs ( 299 , 304 ). These higher emissions induced by climate change would increase the susceptibility of exposed animals and humans via food chain and lead to greater adverse effects on human health and terrestrial ecosystems ( 305 ). While the researcher's grapples with the problem of ever-increasing environmental pollution, at the same time, the causes of climate change and its impacts on the fate and toxicity of chemicals must be addressed.

EDCs influence and modify the hormonal homeostasis and, therefore, it is plausible that their effects will be more pronounced in periods during which marked hormonal changes occur, such as perinatal period, puberty and pregnancy. Tissue differentiation and maturation of several organs occur during these “critical windows” which may be influenced by EDCs ( 236 ). Moreover, the effects of exposure may not be apparent immediately and may take several years to be observable. This is supported by several studies that show the association between several health and behavioral parameters and EDC exposure during these key periods. In utero exposure to several EDCs was found to influence fetal growth and birth weight ( 109 – 112 , 117 ) and also predisposed some individuals to obesity and fat gain during later life ( 17 , 21 , 22 ). Exposure to EDCs during the prenatal and perinatal period has been thought to influence the timing of puberty as well ( 86 , 88 ). Several studies evaluating the neurological development of children have shown association of prenatal EDC exposure with adverse cognitive and behavioral outcomes ( 145 , 146 , 148 , 151 – 153 ). Prenatal exposure to phthalates was shown to alter thyroid homeostasis in pregnant women as well as the offspring ( 167 ). For POPs, latency could be due to long-term continuous exposure. For non-persistent EDCs, exposure could be variable. Apart from the molecular mechanism, epigenetic changes may be important in delayed or latent effects, especially in perinatal exposures.

Over the past several decades, obesity and type two diabetes rates have increased markedly in all age groups worldwide and particularly in developed countries. Obesity is frequently associated with other morbidities such as metabolic disorders (including metabolic syndrome, type 2 diabetes, cardiovascular diseases, pulmonary complications, and liver disease), psychological/social problems, reproductive abnormalities and some forms of cancers. An amalgamation of lifestyle, genetic and environmental factors probably accounts for the quick and considerable increase in obesity rates. An increase in the occurrence of metabolic diseases has been noted in last several decades, which coincide, with the significant changes in the chemical environment around us, which came in practice during the same period. Velmurugan et al. ( 9 ) has demonstrated that the common risk factors for diabetes may not be the sole contributor, while other factors such as production of EDCs (plastics, plasticizers, pesticides, e-waste, food additives) has been found to be positively associated with the growing trend of the global diabetes incidence in last few decades ( Figures 3 , 4 ). Total plastic waste generation by country, measured in million tons per year for the year 2010 and disease burden from non-communicable diseases (from 1990 to 2016). Total disease burden from non-communicable diseases (NCDs), measured in DALYs (Disability-Adjusted Life Years) per year. DALYs are used to measure total burden of disease—both from years of life lost and years lived with a disability. One DALY equals 1 lost year of healthy life. Base map courtesy of mapchart.net ( http://www.mapchart.net ) [Source: ( 10 , 11 )]. Trends of global diabetes, obesity, and plastic production during the period of 1980–2008 [Data source: https://ourworldindata.org/plastic-pollution and ( 9 , 12 )]. This change in our chemical environment seems to be a contributing factor in this “obesity pandemic” apart from genetic factors and modern lifestyle that embraces high energy intake, reduced physical activity, sleep deprivation and near stable home temperatures. This has led to the hypothesis that some of these environmental chemicals disrupt the endocrine process and lead to obesity by interfering with various endocrine aspects of metabolism ( 13 , 14 ). This hypothesis garners support from animal as well as epidemiological studies, which have revealed that a diverse array of environmental chemicals can influence adipogenesis and obesity; however, its extent, exact mechanism and epidemiology are yet to be elucidated. The EDCs linked with obesity and adiposity include several POPs ( 15 – 18 ), BPA ( 19 , 20 ), and phthalates ( 21 – 23 ). It has been suggested that in utero or childhood exposure to certain EDCs predisposes some individuals to obesity, highlighting the importance of timing of exposure ( 17 , 21 , 22 , 24 , 25 ). Such EDCs have been referred to as “environmental obesogens” ( 26 ). The term “metabolic disruptors” has also been suggested as many of these chemicals be associated with other metabolic diseases such as metabolic syndrome, insulin resistance and type 2 diabetes as well ( 17 , 27 ). Several studies have found association of type 2 diabetes and/or its risk factors with PBCs, DDE, organochlorine pesticides, HCB, dioxins, BPA and phthalates ( 28 – 37 ). Some prospective studies have interestingly concluded that no single POP could significantly predict T2D, but some combination of POPs could predict the future risk of T2D ( 28 , 31 – 33 , 38 ). This also lends support to the concern that exposure to EDCs as mixtures that occur in the environment may have greater significance than that to single chemicals tested in laboratories. In addition, several studies have shown association of gestational diabetes to phthalates, BPA and PCB ( 39 – 42 ). Increased risk of non-alcoholic fatty liver disease has been linked to BPA ( 43 ) as well as cardiovascular risk factors are found to be linked to both organochlorine pesticides ( 44 – 46 ) and BPA ( 47 , 48 ). EDCs alter metabolic balance through multiple mechanisms including alterations in peroxisome proliferator-modulated pathways ( 49 ), adipogenesis ( 50 ), pancreatic β-cell function ( 51 – 53 ) and hypothalamic neuropeptides ( 54 , 55 ). In addition, decreased physical activity in relation to whole-body energy balance has been reported in mice that were exposed to BPA either during a perinatal period or in adult life ( 56 , 57 ). However, most of the evidence regarding the mechanism of action of EDCs comes from experimental studies. In a recent study, it was shown that prenatal exposure to BPA and certain phthalates might affect the levels of adiponectin and leptin in human fetus ( 58 ). A novel hypothesis advanced is the role of gut microbiota in EDC-induced type 2 diabetes. It is thought that EDCs not only cause dysbiosis of gut microbiota but also undergo metabolism by gut microbes, and both these processes alter the gut neuroendocrine regulation of metabolism leading to insulin resistance and type 2 diabetes ( 9 ).

Thyroid hormones are controlled through the hypothalamic–pituitary–thyroid axis, and they are vital for the regulation of several biological systems and can be disrupted by EDC exposure. Specifically, the phenols and phthalates are thought to act directly on the thyroid hormone receptor, and studies have shown that these compounds are thyroid receptor antagonists. Epidemiological studies have shown that cognitive functions of the offspring may be adversely affected by even a marginal lowering in thyroxin levels in a pregnant woman ( 163 – 165 ). Thus, exposure to thyroid-disrupting chemicals may have significant consequences for public health even if they bring about a small reduction in thyroid hormone levels. Several studies have evaluated the EDC exposure effect on thyroid hormones in humans. Most of these have explored the effect on pregnant women and new-borns. A study reported that urinary concentrations of phthalate metabolites were seen to be associated with lower T4 and T3 or higher thyroid-stimulating hormone (TSH) levels in adults ( 166 ). In another study, prenatal exposure to phthalates was found to be inversely associated with both total serum thyroxine in pregnant women and newborns as well as TSH in newborns ( 167 ). The association with BPA is more variable in several studies. Two studies found no association between thyroid hormone levels and maternal BPA exposure ( 168 ) and cord blood BPA levels ( 58 ), respectively. Another study reported no association between maternal urinary BPA concentrations and thyroid hormones measured in cord serum when analyzed for all newborns, but they found that in female newborns, lower cord TSH was associated with the 10-fold increased BPA in maternal urine ( 169 ). In the analysis of data from the U.S. National Health and Examination Survey, urinary BPA showed a negative relationship with serum TSH levels in adults ( 166 ), while another European study concluded that a significant positive association was observed between urinary BPA and serum TSH in adult women ( 170 ). A study found that there was a negative correlation between PCB levels and maternal free T3 but not with cord blood ( 171 ). However, a systematic analysis did not find any correlation between PCBs and thyroid hormones in either pregnant women or newborns ( 172 ). In a study including three European cohorts, the researchers concluded that PCB was associated with lower TSH levels in newborns ( 173 ). In another study, in the case of PBDEs, negative correlation was found with maternal and cord blood thyroid hormones ( 171 ), while positive correlation was seen with maternal blood thyroid hormone levels in two other studies ( 174 , 175 ). Organochlorine pesticides were noted to be associated with reduction in thyroid hormones ( 176 ).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Growth is the consequence of a multifaceted interaction of genetic, constitutional, nutritional, endocrine and socio-economic factors as well as psychosocial well-being ( 200 , 201 ). The evidence is seen in the fact that over the last century, children have gradually become taller and are reaching puberty earlier. For example, the age of menarche in European girls in the middle of the nineteenth century was 16–17 years, in contrast to the current age of 13 years or less. Rampant use of sex steroids as growth promoters has occurred in animal farming, which continues in several countries of the world. The timing and evolution of reproductive aging depend mainly on genetic and environmental factors. So far, most research has focused on genetic predispositions ( 202 ). Nevertheless, the environment probably plays a role, and there is an assumption that EDCs may accelerate reproductive aging, resulting in shortened reproductive lifespan. Recent studies show that exposures to EDC during critical developmental periods, particularly during fetal life and early childhood can cause molecular/cellular changes that modify the function of the affected tissues later in life, a concept referred to as the fetal/developmental basis of adult disease ( 203 ). These effects are thought to be brought about by epigenetic modifications. Animal studies show that reproductive aging is accelerated by EDC (MXC) ( 204 ), BPA ( 205 ), and dioxins ( 206 ). Recent epidemiological evidence also links EDC exposures during periods of growth to accelerated menopause [diethylstilbestrol ( 207 ) and perfluorocarbons ( 208 )]. BPA has also been shown to promote oxidative stress and inflammation, and it has been suggested that it makes postmenopausal women suffer health effects related to aging ( 209 ).

More recently, scientists have discovered evidence showing that EDCs can modify gene expression without mutating DNA, which is also known as epigenetic change ( 220 ). The known possible mechanisms of epigenetic changes include methylation of cytosine residues in DNA, post-translational modification of histones and altered microRNA expression. These changes may lead to transgenerational effects on numerous organs and organ systems and are thought to be tissue-specific as well as dose-dependent ( 221 – 223 ). Epigenetic transgenerational inheritance is the phenomenon where environmental exposures of a woman during gestation lead to germline epimutations, which are then transmitted to subsequent generations with an observable phenotypic expression ( 224 , 225 ). BPA is the most widely studied EDC in terms of epigenetic changes, and several animal studies support this theory ( 226 – 228 ). Other chemicals implicated in epigenetic changes leading to transgenerational effects are dioxins ( 229 , 230 ), DDT ( 231 , 232 ), and phthalates ( 233 , 234 ). In addition, the epigenetic changes are also thought to cause latent effects in case of early life exposure, with manifestation later in life ( 235 ). However, most of these studies have evaluated only the effects on the reproductive system of experimental animals. The epigenetic changes add another dimension to understand the complexity and mechanism in the studies of environmental exposures and their effects.

Breakthrough in the mapping of the human genome has laid the foundation of potent tool to classify genes and biological processes underlying any feature influenced by inheritance, including diseases. Now a similar approach can be used for mapping the “exposome”—the aggregate of environmental influences and biological responses throughout the life span ( 292 , 293 ). The major challenge in EDC research is the difficulty in precisely measuring the exposure during critical sensitive windows as well as throughout the lifespan ( 292 ). Emerging technologies in genomics, epigenomics and mitochondriomics are novel opportunities to bridge the gap in exposome measurement and precision in EDC research. Every aspect of the continuously changing external and internal environment ( 294 ) constantly affects Epigenomics, proteomics and metabolomics. Extensive exposome approach will facilitate the assessment of deleterious health effects of EDCs in humans through targeted biomarkers that restructure past environmental exposure and forecast future hazard ( 295 , 296 ).

Most of the information on the detrimental effect of EDCs comes from animal studies. It is becoming more evident that EDCs may trigger disorders such as metabolic diseases, reproductive abnormalities, endocrine dysfunction and cancers. The sudden escalating rates of these diseases, especially metabolic disorders, correlate with global industrialization and the production and release of EDCs to the environment, drinking water and eventually to food chain. Countries should formulate acts and guidelines including EDCs for the safety of drinking water. To understand the exposure routes of EDCs better, a comprehensive assessment of drinking water supply is required. Exposure to EDC or mixtures, even at low doses, especially during critical window or early development can have an impact on endocrine system by altering transgenerational/epigenetic pathway. Hence, further studies are required to establish the threshold concentrations of EDCs in the environment as well as in human matrixes (bio monitoring) below which its detrimental effects do not occur. Large-scale systematic epidemiology studies need to be carried out taking into consideration the low dose effect and cocktail effect of EDCs.

Several biological effects of EDCs are mediated through SHRs ( 210 ). Hormone receptors are high-affinity receptors, that is, a small concentration of hormones or hormone mimickers can produce a significant biological effect. In addition, the dose-response curves of these receptors are non-linear; they can be sigmoidal, or more complex, including being non-monotonic. The non-monotonic dose-response (NMDR) curves are often “U-shaped” (with maximal responses observed at low and high doses) or “inverted U-shaped” (with maximal responses observed at intermediate doses) ( 161 ). EDCs mimic hormones in their actions including low-dose effects and dose-response patterns, which depend on characteristics of their binding receptors and ligands ( 161 ). Due to this property, environmentally relevant concentrations of these chemicals need to be studied thoroughly for their effects on the general population. Several studies have provided evidence that low-dose environmental exposures to EDCs are associated with disorders in humans as well as wildlife ( 17 , 70 , 211 , 212 ). Research shows that many SHR-mediated adverse effects of EDCs may be non-linear or even non-monotonic and such effects commonly occur in dose ranges exerting no overt cytotoxicity ( 213 – 218 ). One of the setbacks due to these non-classical responses is in extrapolating the effect from high doses to low doses or vice versa because there is no linear relationship ( 219 ). Defining safe limits for such chemicals also becomes troublesome. Most of the evidence for NMDR comes from cell culture and animal studies. Several epidemiological studies have also focused their attention on NMDR in EDCs recently but they differ significantly in their conclusions ( 23 , 219 ). However, these differences in conclusions can arise from several inherent drawbacks in human epidemiological studies, for example, cross-sectional vs. prospective design dichotomy and difference in study analysis methods. In addition, there is a lack of sufficient knowledge about kinetics of these chemicals, their interactions with adiposity and diet, and changes to these factors with age and gender. Furthermore, in epidemiological studies, populations are often exposed to a variable mixture of chemicals at various exposure levels for various durations, and predictably, these interactions are complex. These factors make human studies difficult to interpret.

Human beings are exposed to different chemicals through air, water and soil, but oral exposure to EDCs, largely via the food chain, is their key pathway into human metabolism. The gut microbiome comprises trillions of bacteria, viruses and fungi, and it is documented as a main participant in the metabolism of nutritional compounds, drugs, antibiotics and environmental toxins ( 259 – 264 ). Bacterial fermentation of undigested carbohydrates and xenobiotic compounds produces short-chain fatty acids, choline, bile metabolites and several volatile compounds including hydrogen sulfide. The gut microbiome also plays a major role in regulation of various hormones, neurotransmitters and ultimately host metabolism. Some metabolites produced during bacterial fermentation in gut behave as hormones that can affect diverse host metabolic functions, and hence the gut microbiome has been anticipated to be a new endocrine organ ( 265 – 267 ). Dysbiosis of gut microbiome is commonly observed in medical conditions. Concerning diabetes, a shift in the Bacteroidetes / Firmicutes ratio was found to have a key link with plasma glucose concentration ( 268 ). Microbial metabolism of chemicals, as well as EDCs, by gut microbiome can lead to microbial dysbiosis, stimulation of specific bacterial genes, and altered microbial transformation of molecules ( 260 , 268 ). Previous researchers had determined how diet and host health could influence the gut microbiome composition ( 269 – 273 ). On the other hand, several acquired factors encountered on an everyday basis can exert extreme effects on the gut microbiome. Environmental chemicals, such as EDCs, heavy metals and air pollutants are increasingly invasive in terrestrial and aquatic environments, and there is a signal that such chemicals will turn out to be even more profuse in near future ( 274 – 281 ). Such chemicals are also found in things that we use daily, such as plastic water bottles, storage containers, and antibacterial supplies. Introduction to such chemicals can result in extensive host effects and concurrently aim commensal microbes harbor within the gut and perhaps other organs. The chemical-induced dysbiosis of the gut microbiome leads to disruptions in various host systems, mainly the central nervous system, via the gut–microbiome–brain axis ( 282 – 284 ). An improved understanding of how environmental chemical-induced gut microbiome dysbiosis changes strengthen host disease is essential. Disorders associated with gut dysbiosis comprise metabolic, neurobehavioral, immunological, cardiovascular, gastrointestinal and several other disease states ( 273 , 285 – 291 ). The gut microbiomes have a different class of enzymes such as Phase I and Phase II. They can metabolize environmental xenobiotic chemicals and environmental chemicals may cause dysbiosis of gut microbiome, with potential effects on human health. Based on previous studies we may conclude that gut microbiome plays a major role in the toxicity of environmental pollutants.