INTRODUCTION — There is increasing evidence from epidemiologic studies, case studies, and complementary animal and cell-based models that endocrine-disrupting chemicals (EDCs) can have effects on human health. EDCs are exogenous agents that disrupt normal endocrine physiology by interfering with hormone synthesis, metabolism, and/or cellular actions [1,2]. While EDCs exist naturally in soy, legumes, and other plant-based products, their major source results from industrial processes. EDCs are found in air, water, and soil, as well as in numerous household products and medical devices, and have thus become ubiquitous in our environment. As with other environmental contaminants, EDCs can cross the placenta and have now been implicated in the developmental origin of diseases such as obesity and diabetes. Epidemiologic data suggest that the rise in diabetes, cancer, and infertility in the past two to three decades could be attributable, at least in part, to in utero exposure to EDCs [3-7].
The molecular mechanisms of EDC action, as well as their potential association with reproductive and nonreproductive disorders will be reviewed here. The impact of EDCs on female reproduction is also reviewed in a separate topic. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact".)
HISTORICAL CONTEXT — Endocrine-disrupting chemicals (EDCs) can mimic or disrupt the action of natural hormones. EDCs first received widespread attention because of the effects of high-level industrial contamination on the abnormal development of fish, aquatic animals, and birds. Early scientific studies that focused on effects of high-level EDC exposure were largely dismissed for not being relevant to human exposure. However, there is now a body of evidence from epidemiologic, animal, and cell-based studies that the low levels that reflect common, real-world exposures may also have important consequences for human health. EDCs possess estrogenic, anti-estrogenic, androgenic, anti-androgenic, and other hormonal effects and may impact reproductive, developmental, and other health outcomes. Over 1000 individual EDCs have been identified; a complete listing can be found online at The Endocrine Disruptor Exchange (TEDX).
TYPES OF EDCS — Endocrine-disrupting chemicals (EDCs) encompass a heterogeneous group of agents that can be classified as plant-derived, industrial chemicals, manufactured household and consumables, medical supplies, and pharmaceuticals. Some EDCs are included in more than one category.
●Plant-derived (phytoestrogens) – Enriched in flaxseed, nuts, soy products, cereals, breads, and legumes (genistein, daidzein)
●Industrial chemicals – Pesticides, flame retardants (per- and polyfluoroalkyl substances [PFAS chemicals]), combustion products (polycyclic aromatic hydrocarbons [PAHs], dioxins), lubricants (polychlorinated biphenyls [PCBs])
●Household, personal care, and consumable items – Cosmetics, sunscreens, toys, food and beverage packaging materials, contaminated food, contaminated groundwater, tobacco products, tea tree and lavender oils, benzophenone-3 and oxybenzone, bisphenol A (BPA), phthalates, perchlorate, dioxins
●Medical supplies – Intravenous tubing, gloves, bags (BPA, phthalates)
●Pharmaceuticals – Natural and synthetic steroids (diethylstilbestrol [DES], estradiol)
MOLECULAR MECHANISMS OF ACTION — Endocrine-disrupting chemicals (EDCs) can stimulate or inhibit the production and metabolism of endogenous hormones, or disrupt peripheral transport of hormones to their target tissues [8]. The estrogenic and anti-androgenic activities of EDCs are the most well established. There are often significant structural differences between EDCs and endogenous steroid hormones, and therefore, assignment of estrogenic and anti-androgenic properties to individual EDCs is typically established using bioassays. Outcomes of such bioassays, as well as EDC routes of exposure and reported outcomes in humans, are summarized in the table (table 1).
EDCs can act through several different pathways either singly or in combination to alter the function of cells (figure 1):
●Classic nuclear receptor pathway – The most established cellular effects of EDCs are their ability to activate or inhibit nuclear receptor signaling. Nuclear hormone receptors are a family of ligand-modulated transcription factors that manifest their biological effects by interacting with DNA response elements within target genes [9] (see "Molecular biology and physiology of estrogen action"). The receptors recruit coactivator or corepressor proteins to the DNA response elements, enabling them to activate or repress gene expression [10]. EDCs can bind to the ligand binding pockets of hormone receptors for estrogens (ERs), androgens (ARs), progestins (PR), and thyroid hormone (TR) to mimic or disrupt their cellular activities [11]. In addition, the glucocorticoid/mineralocorticoid (GR/MR) system has been identified as a target of EDCs [12]. Many EDCs bind with significantly (>1000-fold) lower affinities [13,14]. The combination of relatively low binding affinities of EDCs for hormone receptors and the relatively high doses required for activation [15] suggest that the adverse effects of these agents may occur through alternative signaling pathways.
●Nongenomic nuclear receptor signaling — EDCs that mimic estrogen action can also activate nongenomic signaling through the seven transmembrane ER, GPR30 (figure 1). Genistein and bisphenol A (BPA) possess considerable relative binding affinities for GPR30 compared with estradiol [16], and both activate GPR30 signaling with similar efficacy as estradiol. Doses between 1 pM and 1 nM of BPA and other EDCs are sufficient to elicit estrogenic effects biologically [17-19]. BPA has been detected at nM concentrations in human adult and fetal serum, breast milk, amniotic fluid, and cord blood [18]. These levels are thus sufficient to activate GPR30, and it is likely that estrogenic effects of BPA are mediated through nongenomic ER signaling rather than the classical pathway [16]. This mechanism may also be relevant with EDCs that affect other nuclear receptors.
●Epigenetic effects – Developmental reprogramming refers to alterations in the epigenome that occur during the prenatal and early postnatal periods. This is a critical window when epigenetic modifications such as methylation of histones and cytosine-guanine sequence [CpG] sites in DNA are made on the genome [20]. There is now evidence that early introduction to EDCs may induce developmental reprogramming in the adult, with a potential to transmit to future generations. It is known that the use of diethylstilbestrol (DES) during pregnancy resulted in significant reproductive abnormalities and rare cancers in offspring [21]. (See "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Females exposed to DES in utero (DES daughters)'.)
There is also emerging evidence that early exposure to BPA and other EDCs may increase susceptibility to chronic diseases in adulthood, including endocrine disorders, diabetes, and cancer [22,23]. One report described the ability of EDCs, through induction of nongenomic signaling, to activate a histone methyltransferase and alter histone methylation patterns of genes associated with prostate cancer. These events occurred during prostate development, and these epigenetic modifications persisted throughout adulthood where they resulted in elevated basal and hormone-induced expression of reprogrammed genes [24].
Epidemiologic studies have found an association between EDC exposure and obesity. Experimental data suggest that polycyclic aromatic hydrocarbon (PAH) exposure in utero results in altered methylation and enhanced activity of the peroxisome proliferator-activated receptor-gamma, the primary regulator of adipogenesis [25], providing a mechanistic explanation for the epidemiologic findings.
HUMAN EXPOSURES
Routes of exposure — Endocrine-disrupting chemical (EDC) exposure can occur through ingestion of food, dust, and water; inhalation of gases and particles in the air; skin contact; biological transfer across the placenta; or from mother's milk.
EDC detection — EDCs accumulate at readily detectable levels in humans. The 2003 to 2004 National Health and Nutrition Examination Survey (NHANES III) conducted by the Centers for Disease Control and Prevention (CDC) found detectable levels of bisphenol A (BPA) in 93 percent of urine samples from individuals 6 years and older [26]. A similar survey of 1000 individuals showed that the majority tested positive for phthalates [27], which are plasticizers found in numerous household, medical, and cosmetic products. EDCs have also been detected in human blood, sweat, urine, breast milk, and hair in both children and adults [28,29].
●Many EDCs are lipophilic and may, therefore, accumulate in adipose tissue in particular, being released into the bloodstream over time [8].
●Importantly, individual environmental substances do not exist on their own, and different classes of EDCs have additive or even synergistic effects [30].
●Intensified effects of combinations of EDCs (usually referred to as mixtures) have been observed in human breast, ovarian, and prostate cells, where normal hormone-dependent growth pathways were perturbed [31].
●Epidemiologic data in humans relating EDC exposure to disease are supported by demonstration of causal relationships in experimental animal models at doses commensurate with human exposures [13,17].
●EDCs frequently do not demonstrate traditional linear or sigmoidal dose-response effects; effects have been seen with very low exposures, particularly during critical developmental windows (eg, "in utero," infancy, puberty) and, thus, no safe dose of EDC exposure can be established.
●There are concerns about EDCs in certain sunscreens. Mineral-based sunscreens (titanium dioxide, zinc oxide) are now recommended over those containing other active ingredients. Sunscreens and other topical agents containing the most widely used ultraviolet chemical filter, oxybenzone (also known as benzophenone, or BP-3), should be avoided as it has been identified as an EDC. Systemic absorption is substantial [32], and there is evidence of adverse brain and breast effects in animal models [33,34]. Human data are not yet available.
EDCs AND REPRODUCTIVE DISORDERS — There is emerging evidence that endocrine-disrupting chemicals (EDCs) can perturb the function of neuroendocrine regulatory systems. The most established effects are on the hypothalamic-pituitary-gonadal (HPG) axis.
Children
Precocious puberty — Children presenting with signs of secondary sexual development younger than the age of 8 years in girls or 9 years in boys require evaluation for precocious puberty. Early puberty may be the consequence of early activation of pulsatile gonadotropin-releasing hormone (GnRH) secretion (central or gonadotropin-dependent precocious puberty) or from endogenous secretion of excess sex steroids or gonadotropins or exogenous sources of sex steroids. (See "Definition, etiology, and evaluation of precocious puberty".)
Feminization, including gynecomastia in boys, has been attributed to excess estrogen exposure from creams, ointments, and sprays. Women using these topical estrogens to treat menopausal symptoms may inadvertently expose children to the hormones. Other possible sources of estrogen exposure include contamination of food with hormones, including phytoestrogens (eg, in soy). Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing creams (see "Definition, etiology, and evaluation of precocious puberty"). Lavender or tea tree oil (both of which display weak estrogenic and anti-androgenic activities in vitro) have been associated with the development of gynecomastia in prepubertal males [35-37] and premature thelarche in young girls [38]. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Herbal products'.)
Pubertal onset in children has been trending earlier in the United States and in most other developed countries. There is some experimental and clinical evidence that the rise in early puberty may be caused in part by EDC exposure [39]:
●Higher serum levels of phthalates have been reported in girls from Puerto Rico with premature thelarche [40].
●High plasma levels of p,p'-DDE, a metabolite of the organochloride pesticide dichlorodiphenyltrichloroethane (DDT), were reported in immigrant girls in Belgium with sexual precocity, but have not been reported in boys [40-42]. While DDT is no longer used in the United States, it is still widely used in Mexico, South America, Africa, and Asia, so the risks of exposure remain concerning.
Women
Reproductive development — Early life exposure to EDCs alters development of the female reproductive system [41-43]. The greatest risk may be during prenatal and early postnatal development when organ and neural systems are forming (as was seen for diethylstilbestrol [DES] exposure). In light of the DES experience, it is concerning that high levels of multiple EDCs have been found in both human amniotic fluid and umbilical cord blood [44]. (See "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Females exposed to DES in utero (DES daughters)'.)
There is also significant concern about the potential impact of early exposure to bisphenol A (BPA). Until its banning by various regulatory agencies [45], BPA was a component of baby bottles, pacifiers, baby food packaging, and infant and children's toys. Epidemiologic data are lagging, but animal data suggest that treatment with BPA at environmentally relevant doses is associated with ovarian cysts, proliferative lesions in the oviduct, vaginal adenosis, cervical sarcoma, uterine polyps, and mammary adenocarcinoma [46]. Available data suggest that BPA is an ovarian toxicant (unlike toxins, which are poisons produced from biological sources, toxicants are synthetic, human-made, toxic products introduced into the environment). BPA has been associated with impaired implantation in women undergoing in vitro fertilization (IVF) [47].
Ovarian function and fertility — Experimental and epidemiologic studies indicate that exposure to multiple EDCs can disrupt several aspects of folliculogenesis. BPA, phthalates, pesticides, and components of cigarette smoke are known to decrease the population of primordial follicles and alter the development of primary, preantral, or antral populations of follicles, or corpus lutea [48-52]. (See "Overview of occupational and environmental risks to reproduction in females".)
Both human and experimental data suggest that EDCs may also disrupt the processes of ovulation and fertilization. (See "Ovarian development and failure (menopause) in normal women", section on 'Ovarian development'.)
●Polychlorinated biphenyls (PCBs) – PCBs are a class of synthetic aromatic compounds that were previously used in lubricants, cutting oils, electrical insulators in construction materials, and machinery. PCBs entered the environment through spills, equipment leaks, and improper disposal and storage before they were banned in the United States in 1978 and worldwide in 2004 [53]. However, because PCBs bind strongly to soil and sediment, they continue to persist in our environment. The most common route of exposure is through food as PCBs are lipophilic and hence accumulate in the fatty tissue of seafood and livestock. High serum PCB levels are still found in adults, where they have been associated with longer menstrual cycles and can result in a longer time to pregnancy [54]. Furthermore, in women undergoing IVF, serum and follicular fluid levels of DDE (a DDT metabolite), were positively correlated with failed fertilization [55].
●Trichlorfon – There are also reports that correlate maternal intake of the insecticide trichlorfon with risk of congenital abnormalities. In one report of Hungarian mothers who had consumed fish contaminated with high levels of the insecticide during pregnancy, 11 of their 15 offspring (73 percent) had congenital anomalies (four with Down syndrome) [56]. Other confounders, including age and consanguinity, were ruled out as possible contributing factors.
●Phthalates – In animal models, exposure to phthalates during pregnancy are associated with decreased rates of implantation, higher rates of miscarriage, and decreased viability of neonates [41]. Other studies of EDCs and human reproductive outcomes are more equivocal, possibly due to small sample size, poor methodology, and multiple confounding factors [57].
A number of EDCs have been shown experimentally to alter biosynthesis of steroid hormones, in particular, ovarian production of estradiol, progesterone, and testosterone [58-60]. Phthalates and pesticides were found to inhibit estradiol production by decreasing steroidogenic enzymes [58,59] and increasing CYP1B1-mediated hormone metabolism [58]. In an animal model, treatment of ovarian granulosa and thecal cells with BPA altered the expression of steroidogenic enzymes and increased production of estradiol, testosterone, and pregnenolone [60].
EDCs may also affect production and release of steroid hormones through an action on gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The hypothalamic peptide hormone kisspeptin is known to regulate GnRH pulse generation, LH and FSH release [61]. Different classes of EDCs are known to interfere with kisspeptin signaling in the hypothalamus [62].
Polycystic ovary syndrome — Polycystic ovary syndrome (PCOS) is a common reproductive disorder in women characterized by oligomenorrhea, androgen excess, polycystic ovaries, and metabolic complications such as insulin resistance and obesity. PCOS is thought to be a complex genetic trait, similar to cardiovascular disease and type 2 diabetes mellitus, where multiple genetic variants and environmental factors interact to foster the development of the disorder. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Pathogenesis'.)
Some have hypothesized that EDCs could be a risk factor for PCOS. Cross-sectional data in women suggest that serum BPA concentrations are higher in those with PCOS compared with normal women [63-65]. In two of these studies, BPA levels correlated with the degree of hyperandrogenemia and insulin resistance [64,65]. It has been proposed that the ability of EDCs to alter steroidogenesis and circulating hormone concentrations may cause the elevations in systemic androgens that are a hallmark of the disease [66] (see 'Molecular mechanisms of action' above). In a rodent model, prenatal exposure to EDCs increased the incidence of polycystic ovaries in offspring [67], although this has not yet been studied in women.
Endometriosis — Endometriosis is a disorder in which there is growth of uterine tissue in other portions of the reproductive tract, causing pain, bleeding, and, in some cases, infertility. It is an estrogen-dependent disease, and thus, EDCs are postulated to have a causative role. The actions could be directly on growth of the lesions or though effects on the immune system, both of which are hormonally sensitive [68,69].
Dioxin is known to stimulate the growth of uterine epithelial cells in vitro [70], and lifetime consumption of a soy diet induces key features of endometriosis in rodent models [71]. Clinical data, however, have been equivocal, and with the existing data gaps, additional studies are required before forming any causative relationships between EDC exposure in humans and the etiology of endometriosis [72,73].
Uterine fibroids — Uterine fibroids are the most common benign tumors of the myometrium. Women typically present with symptoms of abnormal uterine bleeding and/or pelvic pain/pressure. Uterine fibroids may also have reproductive effects, including infertility and adverse pregnancy outcomes (see "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history"). Fibroids require estrogen (ER) and progesterone receptor (PR) activity, and clinical data indicate that both hormones stimulate fibroid growth during the reproductive years [74]. It has been postulated that EDC exposure could play a role in the pathogenesis of uterine fibroids.
Two observational studies reported a higher risk of uterine fibroids in women with a history of in utero exposure to DES [75,76] (see "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Benign gynecologic tumors'). A potential causative link is supported by experimental data in rodent models that have shown that developmental reprogramming by DES and genistein, through changes in histone methylation patterns, causes estrogen-responsive genes in the adult myometrium to become hyper-responsive to hormones. These same epigenetic changes promoted development of uterine fibroids in exposed animals [77].
Men
Reproductive development — In 2001, the term "testicular dysgenesis syndrome" (TDS) was coined to describe the triad of (1) altered fetal reproductive development, (2) decreased semen quality, and (3) testicular germ cell cancer (TGCC). It was suggested that the three disorders share a common pathway by which environmental chemicals and genetics result in abnormal development of the fetal testis [78].
Animal and experimental evidence for an effect of EDCs on male reproduction includes the following:
●Reproductive developmental abnormalities, including hypospadias, cryptorchidism, and oligospermia, have been reported in men exposed to EDCs [8,79].
●Experimental studies of developmental exposure to DES as a model compound for developmental toxicity with associated clinical correlations have shown atrophic effects of DES in the seminal vesicles, mediated by ER-dependent changes in DNA methylation [80]. The atrophic effects could be related to the clinical male infertility seen in DES exposed sons.
Data in men include the following:
●Rates of male reproductive disorders have increased in the human population, as was described above for in utero DES exposure [81-83]. (See 'Human exposures' above.)
●A positive correlation was found between pesticide levels in the adipose tissue of surgical patients with undescended testes [84].
●In contrast, epidemiologic studies examining effects of chemicals used in coolants and pesticides have reported little or no correlation between EDC exposure and developmental malformations [84,85].
Semen analyses
●DDT – Both epidemiologic and clinical data have reported an association between DDT exposure (high serum DDT concentrations) and a decrease in semen volume and sperm concentration, motility, and normal morphology [86,87]. This is particularly true in countries such as Mexico and South Africa, where the pesticide has been used consistently.
●BPA – Epidemiologic studies have correlated BPA exposure with a decline in multiple characteristics of sperm quality [88-90]. Serum BPA concentrations in the men were within the range known to activate nongenomic estrogen signaling through GPR30 [19]; however, the precise mechanism(s) by which EDC activity may affect sperm quality is not well understood. There have also been consistent reports that PCB concentration in adult male serum is inversely proportional to semen quality and, particularly, sperm motility [91-93]. While BPA exposure may be associated with a negative impact on sperm quality [88,89,91-93], one study reported no negative impact on embryo development in the setting of IVF [90].
●Phthalates – Experimental studies have shown that several phthalates possess anti-androgenic activity [94], and thus, it was hypothesized that exposure of males to these chemicals could have adverse effects on fertility. Treatment of pubertal and adult rodents with di(2-ethylhexyl) phthalate (DEHP)-impaired spermatogenesis and caused testicular toxicity [94].
Human phthalate exposure is ubiquitous [8]. Data on reproductive effects in men, however, have been conflicting. Available literature suggests that exposure to phthalates at environmental levels is likely to have minimal effects on classical sperm parameters [95,96]. In a meta-analysis of 20 epidemiologic studies, decline in sperm concentration and motility was associated with detectable serum phthalate in some instances; however, 50 percent of these studies showed no association with semen quality [95]. A cross-sectional study of 420 adult men reported that urinary metabolites of phthalates were not associated with any semen parameter [97].
HORMONE-RELATED CANCERS
Testicular cancer — An important rise in the incidence of testicular germ cell cancer (TGCC) over the past few decades has been observed [98-100]. It has been suggested that lifestyle and environmental factors may play a role, although the evidence is limited.
Results of studies on TGCC risk in men with a history of in utero exposure to polychlorinated biphenyls (PCBs), DDE (a metabolite of DDT), or benzenes are conflicting [101,102]. In the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study, a case-control study of 754 case subjects, serum DDE levels correlated with the risk of both seminomatous and nonseminomatous TGCCs [103], although two smaller case-control studies did not find this association [101,102].
Breast cancer — Lifetime exposure to ovarian hormones is an established risk factor for breast cancer. Not surprisingly, there is concern about the impact of endocrine-disrupting chemicals (EDCs) with estrogenic activities on breast development and breast cancer risk.
●EDC exposure in the intrauterine environment can affect the risk of developing breast cancer later in life. Excess estrogen exposure in utero was associated with elevated breast cancer incidence in twins [104]. Likewise, diethylstilbestrol (DES) daughters aged 40 years and older display a 2.1 greater incidence of breast cancer. In a longitudinal study of women exposed to dichlorodiphenyltrichloroethane (DDT) during pregnancy predicted a nearly fourfold increase in their daughter's risk of breast cancer, independent of a maternal history of breast cancer [97].
●In a study of over 50,000 women in the United States and Puerto Rico who were sisters of women with breast cancer, the use of hair dyes and straighteners was associated with an increased risk of breast cancer, particularly in African American women. Hair products contain over 5000 chemicals, some of which are known EDCs [105]. Additional studies in a more generalizable population are needed.
Data from animal and in vitro models support a possible link between EDCs and breast cancer biology:
●Early exposure to xenoestrogens may result in abnormal mammary gland morphology in rodents, which could predisposed to carcinogenic changes [106].
●In vitro studies of human breast carcinoma cells demonstrate that multiple classes of EDCs cause changes in estrogen-regulated gene expression and upregulation of proliferative pathways [107,108]. These agents also have the potential to induce cancer metastasis through promoting the epithelial-mesenchymal transition and signaling in the tumor stroma in a manner that promotes malignant growth and invasiveness of epithelial cells [109,110].
●There is some controversy whether members of the phytoestrogen class of EDCs have tumorigenic or antitumorigenic effects in the breast. In animals, several phytoestrogens such as genistein and resveratrol have shown preventive effects in experimental systems [111]. Their mode of action may involve dampening the endogenous estrogen receptor stimulatory activities in these tissues.
Prostate cancer — Prostate cancer is the third leading cause of cancer deaths in American men, and an estimated one in seven men living in the United States will develop the disease during their lifetime [112]. (See "Risk factors for prostate cancer", section on 'Environmental carcinogens'.)
Occupational exposure to farming is associated with an increased risk of prostate cancer [113]. Large epidemiologic studies of approximately 90,000 participants showed a direct and highly significant correlation between incidence of prostate cancer and exposure to methyl bromide (a fungicide) and six different pesticides [114,115]. In addition to agricultural chemicals, arsenic, cadmium, and PCBs have been linked to prostate cancer [116]. (See "Risk factors for prostate cancer", section on 'Environmental carcinogens'.)
The precise mechanisms by which these chemicals induce the carcinogenic process in the prostate remain to be resolved, although one shared property is their estrogenic activities. An in vivo model of human prostate stem cells showed that EDCs with estrogenic activities initiate and promote prostatic carcinogenesis in an androgen-supported environment. These findings have led to the hypothesis that tissue stem cells may be direct EDC targets, and developmental or transient adult exposures may cause life-long reprogramming [117,118]. EDC exposure was also found to cause epigenetic changes within several genes involved in prostate cancer initiation and growth [24,119]. These changes involved increased methylation and decreased gene expression.
Moreover, chronically elevated estrogens in men resulting from allelic variants in aromatase have been associated with an elevated risk of prostate cancer [120]. In one report, oral contraceptive use by mothers during pregnancy was positively correlated with prostate cancer risk and mortality in male offspring [121].
EFFECTS ON NONREPRODUCTIVE TISSUES
Obesity and diabetes mellitus — Obesity has reached epidemic proportions both nationally and globally, where it contributes to the risks of heart disease, stroke, and type 2 diabetes. The epidemiology and health risks associated with obesity are reviewed in detail separately. (See "Obesity in adults: Prevalence, screening, and evaluation" and "Overweight and obesity in adults: Health consequences".)
There is evidence the exposure to endocrine-disrupting chemicals (EDCs) may contribute to the development of both diabetes and obesity:
●Some studies have reported a correlation between EDC exposure, body fat, and obesity, prompting the designation of pro-adipogenic EDCs as "chemical obesogens" [122]. Studies suggest that exposure to phthalate could result in nearly 54,000 cases of obesity in older European women [123]. EDC exposures (phthalate and bisphenol A [BPA]) have also been associated with waist circumference [124,125].
●BPA exposure has also been linked to the risk of insulin resistance and type 2 diabetes mellitus in women of reproductive age, including pregnant women [126,127]. Epidemiologic studies have also shown that elevation of urinary phthalate metabolites in women of all ages increases the incidence of diabetes mellitus [128]. (See "Type 2 diabetes mellitus: Prevalence and risk factors", section on 'Environmental exposures'.)
●There may be an association between reproductive and metabolic features of polycystic ovary syndrome (PCOS) and exposure to EDCs, such as BPA [66]. In an animal model, the environmental obesogen tributyltin (TBT) induces reproductive, metabolic, and cardiovascular abnormalities resembling those found in women with PCOS [129]. However, the causal link between TBT exposure and PCOS development remains unclear.
●Exposure to EDCs are also a potential risk factor for obesity in children and adolescents. This is reviewed in detail separately. (See "Definition, epidemiology, and etiology of obesity in children and adolescents", section on 'Other'.)
Cardiovascular and respiratory disease
●Cardiovascular health – Data have emerged relating BPA exposure to risk of cardiovascular disease in children and adults:
•Children born to women with elevated maternal BPA concentrations during second-trimester of pregnancy display significantly higher diastolic blood pressure at age 4 years [130].
•In a 2015 meta-analysis of 33 epidemiological studies, BPA exposure was associated with an increased risk of coronary artery disease and hypertension [125].
•Serum BPA levels may also be a predictor of chronic kidney disease progression in hypertensive individuals [131].
●In contrast, there is evidence suggesting that phytoestrogens can exert cardioprotective effects. The decreased incidence in cardiovascular disease in populations consuming large quantities of phytoestrogens supports this hypothesis [132]. (See "Lipid management with diet or dietary supplements".)
●Respiratory disease – Exposure to agents in common household products, including cleansers, soaps, and cosmetics, can have adverse effects on respiratory health. In addition, an analysis of over 200 commercial products identified over 50 EDCs and compounds associated with asthma, including BPA, phthalates, and benzophenone-3 [133]. Other studies have found associations between polyvinyl chloride (PVC) and asthma/respiratory symptoms [134,135].
PVC can release phthalates into the environment and is one of the most widely produced synthetic plastic polymers. PVC exposure is ubiquitous as the chemical is used in pipes, floors, doors, windows, and many other household products.
Neurologic effects — There are concerns about the potential effects of EDCs on brain function, given the observation of an increase in cognitive, psychiatric, and behavioral disorders over the past few decades [136]. Epidemiologic data suggest that exposure may result in a range of neurologic developmental defects and functional deficiencies in childhood [137]. The PELAGIE mother-child cohort study described neurocognitive deficits in 6-year-old children who were exposed in utero to glycol ethers, chemicals found in cleaning products, liquid soaps, and paints [138]. In the same cohort, prenatal insecticide exposure was associated with both cognitive difficulties and abnormal or borderline social behavior [139,140].
EDC exposure (BPA, phthalates, and others) has been associated with lower grade-point averages in children [141], and polychlorinated biphenyls (PCBs) exposure in utero has been linked to lower intelligence quotients (IQs) [116].
The increase in autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) has focused attention on the possible role of the environment on disease etiology. EDCs are known to induce expression of autism-associated genes, and there is some animal and human data that lead and PCBs may be associated with ADHD risk [142]. However, epidemiologic studies have yielded conflicting results:
●Data from mother-child pairs in the Mount Sinai Children's Environmental Health Study (n = 404), a multi-ethnic urban population, indicated that exposure to prenatal phthalate, but not BPA, was associated with childhood social impairment [143].
●Among 465 children in the Central California Valley, proximity to agricultural organochloride pesticide application in utero was associated with a sixfold increased risk of ASD [144].
●An association between proximity to roadways in utero and ASD has also been reported in a case- control study of 304 cases and 259 controls [145].
●In contrast, the Health Outcomes and Measures of the Environment (HOME) study found no correlation between EDC levels in 175 pregnant women and autistic traits in their offspring [146].
Thyroid disease — Thyroid hormones are essential for normal development, and even transient or mild fluctuations in maternal or fetal hormones are associated with impaired neurodevelopment in the offspring [147]. EDCs are known to impact thyroid function in several ways, including hormone biosynthesis, transport, metabolism, and thyroid hormone receptor (TR) activity [22]. Thus, there is concern that EDC exposure could impair thyroid signaling during development and be associated with the neurologic deficits that have been observed in studies of children exposed to EDCs in utero [147,148]. Polybrominated diphenyl ethers (PBDEs [flame retardants]) exposure has been associated with hypothyroidism (prevalence ratio 1.7, 95% CI 1-3) [149].
Perchlorate, a component of explosives that is a widespread contaminant in drinking water and leafy vegetables, is an inhibitor of the iodide transporter involved in thyroid hormone (triiodothyronine [T3], thyroxine [T4]) biosynthesis (see "Disorders that cause hypothyroidism", section on 'Drugs'). It is found ubiquitously in body fluids of humans (particularly in breast milk).
Perchlorate levels in pregnant women with borderline thyroid function are inversely correlated with cognitive ability in the offspring [148]. BPA, genistein, and PCBs are also known to disrupt thyroid transport proteins and alter the levels and ratio of free versus bound circulating thyroid hormone [150]. Several human studies have correlated increased urinary phthalate concentration to elevations in thyroid-stimulating hormone (TSH) levels [22].
PREVENTION OF EXPOSURE TO SPECIFIC EDCs — Endocrine-disrupting chemical (EDC) exposure is a risk factor in humans for male and female reproductive abnormalities, infertility, cancer, and obesity. EDCs also appear to have an adverse impact on the brain, thyroid, and cardiovascular system. With the increasing evidence that even low-dose human exposure can be harmful, clinicians should be aware of the possible causative link to clinical conditions. Communication between clinicians and patients is critical and should include the following methods to prevent exposure:
●Exposure to bisphenol A (BPA) can be greatly reduced with use of products labeled BPA-free, and the use of glassware for food storage and cooking. The use of BPA-free products is especially important for infants, children, and pregnant women because of evidence for exposure-associated developmental defects. (See 'Children' above.)
●Phthalate consumption can be minimized with use of filtered water and avoiding plastics in food preparation and storage. The use of fragrance-free soaps, detergents, and cosmetic agents also helps to reduce phthalate exposure. (See 'Types of EDCs' above.)
●Mineral-based sunscreens (titanium dioxide, zinc oxide) are now recommended over those containing other active ingredients. Sunscreens and other topical agents containing the most widely used ultraviolet chemical filter, oxybenzone (also known as benzophenone, or BP-3), should be avoided. This agent has been identified as an EDC [33,34] capable of substantial systemic absorption [32]. (See 'Types of EDCs' above.)
●Well water should be tested annually, and pregnant women should use extra precautions in avoiding water sources contaminated with perchlorate. (See 'Thyroid disease' above.)
●Contact with dioxins can be minimized by replacing bleached paper products (diapers, paper towels, tissues) with cloth products (see 'Women' above). Intake of dioxin- and pesticide-contaminated food sources can be greatly reduced by the use of organic products with cloth products.
●Pesticide content can be significantly reduced by peeling produce or by soaking produce for 15 minutes in a sodium bicarbonate (baking soda and water) solution [151].
●The use of topical formulations containing chemicals with estrogenic/androgenic properties, such tea tree and lavender oils, should be avoided for infants, children, and adolescents. When selecting topical products for children, one's pediatrician and/or pharmacist should be consulted as they can provide guidance on the safety of various active ingredients. (See 'Children' above.)
●The frequent consumption of seafood from coastal areas of Europe should be avoided, as fish and shellfish from these areas are known to be highly contaminated with EDCs [152]. It is estimated that the United States imports nearly 30 percent of its seafood from the European Union.
●Individuals who experienced in utero diethylstilbestrol (DES) exposure should have regular examinations to screen for reproductive malignancies. (See "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Pathophysiology of DES exposure'.)
SUMMARY
●Endocrine-disrupting chemicals (EDCs) are a persistent presence in our environment. Analyses of human serum have shown that numerous EDCs are present and readily detected in human body fluids and tissues. The majority of data available on effects of EDC exposure are epidemiologic, and supportive experimental evidence has established a strong causal effect in relation to disorders of multiple organ systems, as well as perturbations in metabolic homeostasis. (See 'Molecular mechanisms of action' above and 'Human exposures' above.)
●Epidemiologic studies are rapidly emerging, which thus far have implied that there are severe clinical consequences of exposure to EDCs during development, childhood, adolescence, and adulthood. However, further data will be required to establish a firm causal relation between EDC exposure and human disease. (See 'EDCs and reproductive disorders' above.)
●There are sufficient findings to suggest that even low-dose exposures have biologic effect, and it is important to take steps to reduce exposure to EDCs, particularly during those developmental periods of life that appear to be most vulnerable to their effects, including the prenatal, perinatal, and neonatal stages and puberty. (See 'Prevention of exposure to specific EDCs' above.)
Reproductive disorders
●Children – Sufficient clinical and experimental data exist to indicate that both prenatal and prepubertal effects of EDCs are manifested in male and female children in the form of premature thelarche and precocious puberty (females) and gynecomastia with exposure to topical agents in preadolescent males. (See 'Children' above.)
●Females – Prenatal exposure to EDCs, particularly diethylstilbestrol (DES) and bisphenol A (BPA), is associated with human female reproductive malformations, as well as cysts, adenomas, and carcinomas in reproductive tissues. Clinical and experimental data also indicate that EDC exposure impacts fertility by interfering with multiple processes including folliculogenesis, steroidogenesis, ovulation, fertilization, and gestation. Consumption of phytoestrogens and estrogen-containing pharmaceuticals increases the incidence of uterine fibroids by promoting estrogen-dependent hyperplasia of the myometrium. Evidence for a link between EDCs and incidence of endometriosis and polycystic ovary syndrome (PCOS) is speculative at this time. (See 'Women' above and "Overview of occupational and environmental risks to reproduction in females".)
●Males – Data from vertebrate experimental animals and humans provide compelling evidence that early exposure to multiple classes of EDCs may result in human reproductive deformities. This is substantiated by the reproductive malformations seen in DES sons. Clinical data indicate that postnatal exposure to dichlorodiphenyltrichloroethane (DDT)-containing pesticides and the plasticizer BPA is associated with significant decreases in sperm quality. This is a significant public health issue given that numerous regions of the world still use pesticides containing DDT, and BPA is abundant worldwide in thousands of daily household and medical products. (See 'Men' above and "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals", section on 'Males exposed to DES in utero (DES sons)'.)
Hormone-related cancers
●The available clinical and experimental evidence indicates that in utero exposure to EDCs increases the risk for breast and possibly testicular cancer later in life. Occupational exposure to EDCs is also associated with an elevated incidence of prostate cancer. The molecular mechanisms of carcinogenesis of EDCs may involve their estrogenic and androgenic activities in addition to epigenetic changes resulting in upregulation of proliferative and metastatic pathways later in life. (See 'Hormone-related cancers' above.)
Nonreproductive effects
●Human exposure to multiple EDCs (BPA and phthalates) is associated with greater incidence of obesity and insulin resistance. BPA is also strongly linked to development of cardiovascular disease, including hypertension in children and adults, coronary artery disease, and possible chronic kidney disease later in life. EDC exposure in utero is a risk factor for autism spectrum disorders (ASD) and lower intelligence quotient (IQ) in children. There is sufficient correlative evidence in humans to advise that EDC exposure be minimized during pregnancy, breastfeeding, and early in childhood because of the risk of these agents interfering with brain development either directly or by disrupting the thyroid hormone signaling axis. (See 'Effects on nonreproductive tissues' above.)
Prevention of exposure to specific EDCs
●There are a number of strategies for prevention of exposure to specific EDCs. (See 'Prevention of exposure to specific EDCs' above.)
As examples:
•Mineral-based sunscreens (titanium dioxide, zinc oxide) should be used rather than those containing other active ingredients. Sunscreens and other topical agents containing the most widely used ultraviolet chemical filter, oxybenzone (also known as benzophenone, or BP-3), should be avoided. This agent has been identified as an EDC.
•Exposure to BPA can be greatly reduced with use of products labeled BPA free, and the use of glassware for food storage & cooking. The use of BPA-free products is especially important for infants, children, and pregnant women because of the evidence for exposure-associated developmental defects.
