The authors have declared that no competing interests exist.
Genetics alone cannot thoroughly expound the environmental impact on the molecular complexity of the endocrine system. Epigenetic-induced alteration in gene expression has emerged as a way in which environmental compounds may exert endocrine effects. The environmental compounds that interfere with normal endocrine signaling are one of the largest classes of toxicants we are exposed to, on a daily basis. Epigenetic mechanisms, mainly the methylation of DNA and the modification of histones, lead to differentiated activation and deactivation of genome domains creating phenotype plasticity and divergent endocrine function among populations and individuals, as well. The issues examined in the present review are related to environmental epigenetics, and more precisely, the epigenetic-mediated modulation and relevance of endocrine disrupting chemicals, focusing on three broad aspects: 1) persistence of EDs, 2) their major hormonal effects and 3) the potential of compounds previously considered as endocrine disruptors to induce epigenetic effects. Evidence suggests that environmental exposures notably impact expression of endocrine-related genes and, thus, affect clinical endocrine outcomes.
There are plenty definitions that attempt to explain what an “Endocrine disruptor” (ED) is. The United States Environmental Protection Agency (US EPA), the World Health Organisation (WHO), the European Union (EU), a joint expert group formed by representatives of the German Bundesamt fuer Risikobewertung (BfR) and health authorities in the United Kingdom (UK-BfR) have proposed similar definitions all of which are considered as appropriate
The mammalian endocrine system consists of a number of distinct hormonal systems including hormones derived from the thyroid gland or other organs such as pancreas, or even brain. Hormonal activity should not necessarily be considered as beneficial or harmful. Their biological contribution can be neutral, as well
EDs steroid function and their androgenic, estrogenic and antiandrogenic activity has been investigated further than their ability to disrupt signaling pathways regulated by hormones of a different nature such as peptide hormones
EDs can act on the epigenome in various ways
Genistein is a well-studied phytoestrogen and its impact on DNA methyltransferases (DNMTs) has been found to be among its epigenome modifying abilities
Polychlorinated biphenyls (PCBs), which have a number of uses such as
Many genes are known to be hormonally regulated, including the family of kallikrein-related peptidases (KLKs)
Soy products are foods with high phytoestrogen content and are substantial components of vegetarian diets
Genistein is found in a number of leguminous plant foods. Phytoestrogens are found in high amounts in soybeans, flaxseed, alfalfa and other edible plants. First of all, soybeans contain high protein levels and the greatest amount of genistein. It can also be found in small amounts in garbanzo beans. Variable amounts of genistein are present in soy protein isolates (SPI), soy milk, soy flour, textured soy protein, tempeh, tofu, and miso. 53% soy protein is found in soy flour while 50-70% soy protein can be found in soy-made meat substitutes such as sausages, hot dogs, hamburgers, meatballs and meat loafs. Other sources of soy protein are SPI, used in infant formulas, sports drinks, energy bars and may contain 90% soy protein
There is a thriving market promoting soy and soy-based foods and formulas addressed to infants. These foods have extremely high circulating levels of genistein indicating the absorption of genistein from soy formulas
Isoflavones in adults vary depending both on ethnicity and diet. Vegetarian women have the highest level of serum genistein while for Asian women the level is slightly lower. Non vegetarian women’s serum genistein is considerably lower than the previous groups
Regarding its chemical structure, genistein resembles stereochemically human endogenous estrogen (E2)
These compounds have structures similar to mammalian estrogens and display both estrogenic and anti-estrogenic effects. Soy isoflavones are able to bind to the ER and induce estrogen-like effects both in vivo in animals as well as in humans. Moreover, it can be applied in vitro in cell cultures. Compared to animal estrogens, phytoestrogens are relatively weak but the relative estrogenic potency is dependent on the type of hormonal activity measurement, dosage, animal species, route of administration and on the duration and timing
Genistein contributes to protection against the development of cancer. Through the demethylation of genes p16, O-6-methylguanine-DNA methyltransferase (MGMT), GSTP1, retinoic acid receptor beta (RARB) and mutL homolog 1 (hMLH1), that exert tumour suppressor function, genistein inhibits angiogenesis and proliferation, two major cellular processes. Rajvir Dahiya and his colleagues have found that genistein affects various miRs, such as miR-1260b, causing histone modification and demethylation of DNA and, consequently, upregulating secreted frizzled related protein 1 (SFRP1) and SMAD4 in Pca cells
Shahana Majid et al., demonstrated a new role for genistein in prostate cancer. BTG3 is a potential tumour suppressor gene that is downregulated in prostate malignancy. Genistein has been found to reactivate the hypermethylated BTG3 gene by the demethylation of its promoter. More specifically, it prompts the demethylation of CpGs, the decrease of DNMT, the inhibition of the activity of methyl-CpG binding domain protein 2 (MBD2) and subsequent induction of prior silenced BTG3 gene
A possible mechanism that regulates gene transcription is the methylation of DNA and the acetylation of histones
The evidenced hypomethylation in the E2F-1 sites leads to increased attachment of the repressor to this binding site, suggesting a cooperation between genetics and epigenetics in the modulation of hTERT transcription when this phytoestrogen compound is present
Thus, genistein could be combined with an epigenetic modulator in order to reach its full epigenetic potential in controlling telomerase’s action in breast malignant cells
Neonatal exposure in DES/Genistein evokes an adult-onset modification in uterine epigenome. Nsbp1 contribution in chromatin restructure and transcriptional function accompanied with the evidence that Nsbp1 transcription is defined by an epigenetic mechanism mediated by estrogen signals, encourages the theory of Nsbp1 participation in tumorigenesis after neonatal exposure to DES/genistein
Normally, in mice without genistein-treatment, Nsbp1 expression is weak prior to puberty. Estrogenic hormones, more specifically estradiol, cause the silence of Nsbp1. However, neonatal exposure to genistein and the co-occurrence of ovarian hormones cause Nsbp1 to get expressed actively throughout life. Neonatal genistein/DES treatment is evidenced to result in promoter hypomethylation of Nsbp1. Consequently, through a mechanism that possibly prevents the silencing of Nsbp1, uterine cancer incidence could increase at some point afterwards
In 1938, a nonsteroidal estrogen, called DES, was synthesized in the United States to prevent miscarriage and other pregnancy complications. It was used as an estrogen for decades and its effects continue to be evident
DES was used until 1971- in which year the Herbst paper appeared in the medical literature and the U.S. Food and Drug Administration (FDA) issued a warning about the
Despite the information that DES was a human carcinogen operating through a previously unknown mechanism, it continued to be used in clinical trials. DES reduces testosterone levels facilitating the treatment of advanced prostate cancer. Moreover, it is used in the treatment of postmenopausal breast cancer
As a xenoestrogen, DES has a similar receptor affinity to the naturally occurring estrogen (estradiol) activating the ER-alpha (ERa). It has a significant oral activity as an estrogenic substance and invokes a strong hormonal response equivalent to an injected dose of the steroidal estradiol-17β
In breast cancer, a miRNA gene, MIR-9-3, is usually hypermethylated. miR-9-3 is an apoptosis modulator. Consequently, the silencing of the gene through an epigenetic mechanism could lead to the proliferation of cancer cells
Hoxa10 gene expression can be modified by deviant DNA methylation after in utero DES exposure. DES, through a molecular mechanism that includes gene methylation, induces developmental changes in the programming of the reproductive tract
There is the so called 'second hit model' which is concerned with the impact of neonatal DES exposure to uterine adenocarcinoma development in adulthood
Estradiol modulates the transcription of HOTAIR. This antisence transcript participates in silencing of genes and plays an important role in breast cancer. More specifically, it has been reported that in breast cancer cell lines the administration of BPA and DES prompts the expression of this long non-coding RNA. HOTAIR expression is upregulated in rat mammary glands upon treatment with BPA and DES, as well. According to Luciferase assay, the promoter EREs of HOTAIR (to a greater extent ERE2 and ERE3) are triggered by DES and BPA, suggesting their potential involvement in endocrine disruption mediated via BPA and DES. The attachment of the MLL family of histone methylases and ERs (MLL1 and MLL3) to HOTAIR promoter EREs induced by BPA and DES causes chromatin modification (H3K4-trimethylation, histone acetylation), which is crucial for gene activation. ERs knockdown leads to decreased DES and BPA mediated HOTAIR expression. In summary, it is demonstrated that HOTAIR expression is epigenetically induced by DES and BPA, without the presence of estrogen being necessary
Bisphenols (BPs) constitute a broad group of chemicals. BPA (2,2-bis-(4-hydroxyphenyl)propane;) is largely used as a monomer in the production of polycarbonates (PC), of epoxy resins and as an additive in other polymeric materials
Epoxy resins mark the introduction of BPA to mainstream production. They were initially applied in food and drink industry to protect the products from the metal packaging since epoxy resins have been used as internal protective coatings in cans for food and beverages and in drinking water storage tanks. BPA is used to make polycarbonate plastics, such as baby bottles
According to existing studies, the route of human exposure to polycarbonate plastics is through epoxy resins and other substances related to foods and drinks
BPA is a chemical acting as a xenoestrogen
BPA applied in utero or neonatally affects body weight, increases susceptibility to prostate and breast cancer and prompts changes in the reproductive function. BPA affects, to a greater extent, epigenetic mechanisms in early development i.e., stem cell stage. There is evidence supporting the enhancement of yellow coat colour of viable yellow agouti (Avy) in mouse offspring, after maternal exposure to BPA
PDE4D4, which plays a regulatory role in cyclic adenosine monophospate breakdown, was analyzed in detail to determine its epigenetic response to estrogen exposure neonatally. 5′-flanking CpG Island of PDE4D4 was the methylating target of BPA and estradiol
PBDEs are widely used as additives to plastics, furniture, textiles, electric cable insulation, water and sewage pipes, office equipment and electronic devices and for fire retardancy reasons i.e., to prevent and retard the spread of fire
Regarding their chemical structure, PBDEs have two phenyl rings linked by an ether bond. The position and number of the bromine atoms results in 209 possible compounds, referred to as PBDE congeners. Technical PBDE products are produced by brominating diphenyl ether when a catalyst is present
In humans, exposure to PBDEs can lead to disturbances in thyroid hormones. The associations appear to be life stage and dose dependent. It has been suggested that PBDEs possibly exhibit hyperthyroid effects
Darnerud and his colleagues have reported that PBDE-209 increases the incidence of hepatocellular carcinomas
Tumor necrosis factor alpha (TNFa) is a gene involved in inflammations and its methylation status gets affected by exposure to environmental PBDEs, even perinatally
Autism is a neurodevelopmental disorder which could be caused by a combination of external factors and genetic susceptibilities. Rett syndrome (RTT) shares autistic traits, and the MECP2 factor plays a regulatory role in the epigenome of this X-linked autism spectrum disorder (ASD)
TCDD, a potent environmental toxicant, evokes adverse health effects in a pattern defined by the gender, the tissue, the life stage and the species. It also prompts modification in the transduction of estrogen signals. Adverse health effects include hepatotoxicity, teratogenicity, cancer, severe anorexia-like wasting. It could even lead to death
Dioxins, like other chlorinated forms, accumulate in food source sequences (bioaccumulation)
TCDD is degenaration resilient and lipophilic, and its properties make it able to accumulate in the adipose tissue, as well
TCDD-exposed preimplantation embryos were transferred to unexposed recipients (mice). On Embryonic Day 14, the aforementioned TCDD exposed fetuses gained less weight than the unexposed controls. The levels of expression of the imprinted genes Igf2 (insulin-like growth factor 2 gene) and H19 decreased after preimplantation embryos’ exposure to TCDD. It is evidenced that in the imprint region H19/Igf2, the methylation was increased in TCDD exposed fetuses and embryos compared to the controls. Moreover, TCDD caused an elevation in methyltransferase activity. Thus, exposure to the environmental toxicant TCDD at the preimplantation stage affects imprinted genes altering their DNA methylation state, influences their expression level in early development, and the altered methylation status is maintained throughout the fetal stage
TCDD possibly mediates in the development of endometriosis. This endocrine disruptor could participate in transcription activities at variable levels, even in the epigenetic one
It has also been reported that progesterone sensitivity can be debilitated by TCDD as it prompts epigenetic alterations with the contribution of toxicant-exerted inflammatory processes
Recent studies demonstrate that TCDD exposure leads to stable and heritable changes in sperm DNA methylation in male rats
PCBs were initially synthesized in the 1930s to be used as lubricants in capacitors and adaptors and, also, as pesticides, hydraulic fluids or plasticizers
So far, 209 possible congeners of PCBs with different biological activities have been recorded. These congeners could be categorized into dioxin- and non-dioxin-like, DL and NDL respectively, depending on their molecular structure. Both of these types are abundant in the environment. DL PCBs activate AHR by attaching to it, just like dioxins do, whereas the so called NDL PCBs elicit minor AHR activity
PCBs are organic chlorine compounds, highly lipophilic and chemically stable. They undergo limited catabolism after absorption and accumulate in the liver and adipose tissues. In addition, PCBs and their metabolites are easily transferred to the fetus through the placenta
PCBs lead to toxicity in fetals when exposed prenatally and predispose children to poor health. When fetal cells get exposed to PCBs during the period of pregnancy they become susceptible to cytotoxic effects as well as genotoxic ones. Cell lines were examined at specific time points during a period of time, in order for global methylation levels and other cellular processes to be evaluated in response to PCB administration
PCBs can modify epigenetic mechanisms
It has been reported that exposure to reconstituted PCB compounds during gestation prompts Jarid1b expression (a demethylase) as well as Sirtuin1 (SIRT1) (a deacetylase)
Developing brain DNA methylation potentially contributes in developmental PCB-mediated neurotoxicity. DNMT activity is decreased in mouse preimplantation blastocytes
PFOA is one of the principal PFCs that are widely used in industrial and everyday consumer products including textile coatings, flame retardants, surfactants, food packaging items and lubricants
Estrogenic signaling probably induces PFOA mediated tumor development in trouts in a peroxisome proliferation independent manner
There has been one epidemiological study evaluating associations between PFAAs and the methylation of DNA. Environmental exposures lead to aberrant methylation motives in circulating fetal DNA. Prenatal exposure to perfluoroalkyl chemicals, such as PFOA, is likely to induce global DNA hypomethylation in cord serum
PFOA prompts GSTP altered methylation. It is known that GSTP is hypomethylated in the disease-free tissue. On the other hand, it is transcriptionally silenced and hypermethylated in human liver and prostate cancer cells as well as in leukemia cells
GSTP promoter contains two SP1 (specificity protein 1) TF binding recognition sites that are very important cis-elements as they are required for the basal activity of the gene
DNMT3A is the potential basal contributor to GSTP excessive hypermethylation since DNMT3B and DNMT1 mRNA transcript levels have been found to be unchanged
As is tasteless, odorless, colorless and even at high concentrations, human exposure to it is not easily avoided
The presence of As in surface soils is either natural or artificial. Anthropogenic activities e.g. mining and metallurgical activities affect the toxic heavy metal content of agricultural soils. Artificial presence refers to the introduction of As by herbicides and long term watering with As burdened irrigation waters. Natural presence refers to As already present within the soils
As activates or inhibits responses, maintaining, probably, the same action mechanism. In low doses As effect is stimulatory. In rat hepatoma cells (EDR3) 0.05–1 μM (6–120 ppb) of As, with the mediation of glycocorticoid receptor (GR), was found to induce gene activation of both the endogenous tyrosine aminotransferase (TAT) and other reporter genes
In the same way, in the NT2 human embryonic carcinoma cells and in the GH3 rat pituitary tumor cells a biphasic response was revealed similar to the one observed for steroid receptors, on genomic-mediated induction by the retinoic acid receptor RAR and the TR
Breast cancer MCF-7 cell line was used to explore As impact on ER
Concerning to estrogenic effect and inhibition of spermatogenesis, As inhibits estradiol binding, possibly by activating ERa through the construction of a high-affinity cluster with the receptor’s hormone binding site. It was shown that in utero As exposure leads to marked alterations in gene expression in fetal liver involving a complex interplay between steroid metabolism and estrogen signaling pathways
After reporting spermatogenic degeneration in animals treated with estradiol, Jana et al. (2006)
Ιn a study conducted by Jana et al., male Sprague Dawley rats were administered 5 mg/kg sodium arsenite in drinking water for 6 d/wk, for 4 wk. The findings showed an alteration in the reproductive activity of the treated animals and, more specifically, reduction in testicular mass and decrease in plasma concentrations of testosterone and gonadotropin
PLA2G2C expression leads to a phospholipase, an enzyme participating in phospholipids’ hydrolysis and their conversion into lysophospholipids and fatty acids
The methylation levels seemed to increase at cg04605617 (chr1: 20,501,558) corresponding to higher As exposure. This locus of PLA2G2C is in its first exon. This locus have been mildly associated with elevated PLA2G2C gene expression. PLA2G2C locus methylation was the determining locus that was correlated with both blood and urinary As concentrations compared to other genes examined
SQSTM1 is involved in a variety of diseases such as cancer, neurodegenerative diseases, insulin resistance and obesity
SLC4A4 expression leads to a sodium bicarbonate cotransporter that participates in the modulation of bicarbonate absorption and secretion and intracellular pH as well. SLC4A4 is, also, associated with decreased body weight/size and abnormal ion homeostasis in mice. Gene mutations of SLC4A4 are related to hypertension
Serum immunoglobulins appear to be increased under the presence of As
PAH are pervasive in our environment and are widely distributed all over atmosphere
Regarding their chemical structure, PAHs consist of 2 to 7 fused aromatic rings
PAHs are considered as EDs because they mimick endogenous hormones, interfering consequently with the organisms’ homeostasis. Schraplau et al., 2015
Moreover, PAHs are either estrogenic or anti-estrogenic depending on the types and locations of the samples. However, the mechanisms responsible for their activities still remain unclear. The analyses of specific PAHs lead to several possibilities such as a direct interaction between PAHs and ERs (estrogenic), AHR-mediated suppression of estrogenic activity (anti-estrogenic), and modulation of estrogen or other signaling pathways (estrogenic or anti-estrogenic)
PAH exposure transplacentally can possibly cause methylation in ACSL3 5′CGI of umbilical cord’s blood cell
IFNγ is a well known asthma-related gene. The gene methylation status is affected in umbilical cord blood cell in response to maternal PAH exposures
PAH exposure results in altered methylation of the Foxp3 promoter region
Perinatal exposure to PAHs can lead to persistent alterations in fat mass, body weight and in the size of adipose cells of F1 and F2 generations
Anopheles mosquitoes are a public health hazard in tropical and subtropical areas since they can cause malaria
DDT is an issue still relevant for many reasons. First of all, DDT was widely used in the past affecting persistently women’s health by increasing the risk of breast cancer, even in contemporary society as the generation of women born during this period of extreme DDT use is alive
The increase in reports of abnormalities in male sex development in wildlife and humans coincided with the introduction of “estrogenic” chemicals, such as DDT, into the environment. This, probably, reflects the AR-mediated antiandrogenic function of DDT metabolite dichlorodiphenyldichloroethylene (p,p'-DDE)
p,p'-DDE-induced sex development abnormalities in males may are AR-mediated. Although ER is considered to induce these phenotypic alterations, AR- mediated events are also consistent with inhibition. p,p'-DDE has a slight ability to attach to the ER, nonetheless it has been found to restrain androgen attachment to the AR, androgen induced transcription and androgen action in growth stages of male rats
The male reproductive system is susceptible to the antagonistic effects of DDT metabolite as p,p'-DDE prompts inhibition of AR-androgen binding and subsequent inhibition of transcriptional activity. AR transcriptional activity in cell culture requires a lower concentration of p,p'-DDE compared to the levels that accumulate in the environment, and more specifically, in areas where DDT remains in use or is present in contaminated ecosystems. In the mid-1960s, period during which DDT was widely used, p,p'-DDE levels were found in tissues from stillborn infants suggesting a way of transplacental route. Indeed, in vitro rat model confirmed the risk of perinatal exposure of infants
Along a period of a month, DDT was administered by gavage to male young rats at doses of 0, 0.006, 0.06, 0.6, 6, and 60 mg/kg/day. According to Shutoh Y et al., a low dose of DDT (0.06 mg/kg/day) is considered to be hormetic. It can induce transcriptional down-regulation and DNA hypomethylation in the young hypothalamus
Epigenetic mediated transgenerational inheritance caused by environmental factors, potentially contributes to obesity induction as well as other associated diseases
DDT was inversely associated with global methylation levels in a study conducted on humans
Fungicides have a variety of applications such as on landscapes, golf courses, industrial activities, lawn turf, and woody ornametals; thus, they can be readily spread to water supplies
Vz is an environmental compound acting as an anti-androgen. Anti-androgens exhibit a mechanism which is determined by interaction with the hormone receptor
Vz and its active metabolites, M1 and M2, principally bind competitively to AR, thereby antagonizing the binding of natural androgens to the receptor
Transgenerational inheritance of acquired traits can be derived either from a chromosomal or from an epigenetic modification. A brief prenatal exposure to vinclozolin or methoxychlor (which is an estrogenic chemical) during the sex determination stage has been found to cause adult decreased spermatogenic capacity and elevated infertility until up to the fourth generation. These effects were correlated with modified DNA methylation in germ line
The transgenerational actions of Vz appear to involve an epigenetic (i.e. DNA methylation) reprogramming of the male germ line
This review has made an attempt to describe emerging pollutants in the environment, EDCs, the major endocrine effects of these compounds and their relevance to epigenetics. People often ignore EDs and, also, the effects of EDs are not readily discerned. The report of EDs and their potential epigenetic actions has not been completed yet. There is an increasing production of chemicals that probably mediate epigenetic mechanisms to disrupt endocrine system’s function. As far as we know, even though epigenetic mechanisms induced by the EDs may differ, DNA methylation is the most common, due to its heritable nature, stability, and ease of measurement. EDs might disturb endocrine mechanisms working in an epigenetic fashion and by mediating nuclear receptors. Further studies are required to explore the procedure by which EDs are capable of altering the epigenome.
A1254, Aroclor 1254; ACSL, acyl-CoA synthetase long-chain; ACSL3, acyl-CoA synthetase long-chain family member 3; ACSL3, acyl -CoA synthetase long -chain family member 3; Agr2, Anterior gradient protein 2; AHR, aryl hydrocarbon receptor; AIT, Dorsal prostate tumor derived cell line; AR, androgen receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; As, Arsenic; Avy, Agouti viable yellow; Avy, Viable yellow Agouti; BaP, benzoapyrene; BBC, Boston Birth Cohort; BDE-47, 2,2'- ,4,4' Tetrabromodiphenyl ether; BfR, Bundesamt für Risikobewertung; BPA, Bisphenol A; BPs, Bisphenols; C, Constant; cAMP, Cyclic adenosine monophosphate; COX, Cyclooxygenase 2 ; COX2, cyclooxygenase -2; CRP , C -reactive protein; Cyp2a4, cytochrome P450; D, diversity; DDE, Dichlorodiphenyldichloroethylene; DDT, Dichlorodiphenyltrichloroethane; DES, diethylstilbestrol; DL, dioxin -like; DL, dioxine -like; DMDs, differentially methylated domains; DNMT, DNA methyltransferase; E2, endogenous estrogen; ED, Endocrine disruptor; EDC, Endocrine disrupting chemical; EDCs, Endocrine disrupting chemicals; EPA, US Environmental Protection Agency; ER, estrogen receptor; EU, European Union; FDA, Food and Drug Administration; FSH, Follicle -stimulating hormone; Ghr, ghrelin and obestatin prepropeptide; GR, glucocorticoid receptor; GSTP, Glutathione S -transferase Pi; HAT, histone acetyltransferase; hMLH1, human mutL homolog 1; hTERT, human telomerase reverse transcriptase; IAP, intracisternal A particle; IFN?, interferon gamma; IgE, immunoglobulin E; IGF, insulin like growth factor 2; Krt1-19, keratin 1 -19; LH, Luteinizing hormone; MBD2, Methyl -CpG P168 Binding Domain Protein 2; MCF7, Michigan Cancer Foundation-7 human breast cancer cells; MCF-7, Michigan Cancer Foundation -7; MECP2, methyl -CpG binding protein 2; MeDIP, methylated DNA immunoprecipitation ; MGMT, O6 methylguanine methyltransferase; miRNAs, microRNAs; MR, mineralocorticoid receptor; N2a, Neuro2a cells; NBE1, normal prostate epithelial; NDL, non -dioxin like; NGS, next-generation sequencing; NF-kB, nuclear factor kappa -b; NF-kB, nuclear factor kappa light chain enhancer of B cells; NR, nuclear hormone receptor; NSBP1, nucleosomal binding protein 1; PAHs, Polycyclic aromatic hydrocarbons; PBDEs, Polybrominated diphenyl ethers; PC, polycarbonates; Pca, Prostate Cancer; PCBs, Polychlorinated biphenyls; PDE4D4, Phosphodiesterase type 4 variant; Peg3, paternally expressed 3; PFCs, perfluorinated compounds; PFOA, Perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; PLA2G2C, Phospholipase A2; POPs, Persistent organic pollutants ; PPARc1, peroxisome proliferator -activated receptor -gamma 1; PR, progesterone receptor; RARß, Retinoic Acid receptor beta; RTT, Rett syndrome; SA, Sheep Amniocytes; SEF, Sheep embryonic fibroblasts; SEF, Sheep Embryonic fibroblast; SFRP1, Secreted frizzled -related protein 1; SIRT1, Sirtuin 1; Snrpn, small nuclear ribonucleoprotein polypeptide N ; SP1, specificity protein 1; SPI, Soy protein isolates; sPTB, spontaneous preterm birth; TAT, tyrosine aminotransferase; TCDD, 2,3,7,8 -Tetrachlorodibenzo -p -dioxin; TCDD, 2, 2 7, 8 tetrachlorodibenzo -p -dioxin; TFs, transcription factors; TFs , transcription factors; Th2, T helper cell type 2; TNFa, tumor necrosis factor alpha; TR, thyroid hormone receptor; Tregs, regulatory T cells; Tubb3 , tubulin beta 3; UCWBC, umbilical cord white blood cell; UK-BfR, United Kingdom Bundesamt für Risikobewertung; UTR, untranslated region; V, variable; VZ, vinclozolin; Xist, X -inactive specific transcript.