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 1. However, the definition provided 1 for endocrine disrupting chemicals (EDCs) by the US EPA is the most suitable to convey their essence in this review as it highlights their role in interfering with natural homeostasis and developmental processes-related hormones, affecting their behaviour or production.

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 1. Hormonal activity is a significant health risk only when resulting in adverse outcomes such as carcinogenicity or reproductive and developmental defects 1.

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 2. Endocrine activity is partly epigenome-shaped, and exposure to EDs is a key factor for this procedure 3. EDs can modulate the direction of epigenetic regulation through their effects i.e., indirect, direct or metabolites; in some cases, EDs can also act transgenerationally 2.

EDs can act on the epigenome in various ways 4. They can alter histone-modifying enzymes’ level of expression or catalytic power 5, affecting consequently the entire endocrine system. The transcription of genes and the arrangement of DNA in chromatin compacts can be regulated by the interaction of histone modifying enzymes with nuclear steroid receptors 5. Such an interaction is the expression of the target genes of histone demethylases, through the involvement of these enzymes in protein clusters and, more importantly, with androgen receptors (AR) 5.

Genistein is a well-studied phytoestrogen and its impact on DNA methyltransferases (DNMTs) has been found to be among its epigenome modifying abilities 56. Diethylstilbestrol (DES), a synthetic estrogen, and bisphenol A (BPA), a plasticizer, can both alter DNA methylation in animals 24. Polybrominated diphenyl ethers (PBDEs) are fire retardants that affect hippocampal neurons reducing global DNA methylation 789. Dioxins, such as 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD), act on preimplantation embryos by altering the DNA methylation of imprinted genes H19/insulin like growth factor 2 (IGF2) 101112. Moreover, TCDD can slightly affect microRNA (miRNA) levels in the liver of adult rodents 5. miRNAs are molecules that exert epigenetic regulation by regulating gene expression 13. For instance, epigenetic regulation of ITGB4 by miR-21 is a key event in colorectal cancer 14; other important miRNAs in this malignancy include miR-15a-5p 15, miR-16 16, miR-24-3p 17, miR-28-5p 18, miR-34a 19, miR-96 20, miR-182 21, and miR-224 22. Several other miRNAs that regulate gene expression have been described as important epigenetic regulators 232425.

Polychlorinated biphenyls (PCBs), which have a number of uses such as 26 in capacitors and in engines and are widely spread in the environment 27, can lead to irreversible DNA methylation 28. Perfluorooctane sulfonate (PFOS) and perfluorooctanesulfonic acid (PFOA), which were the dominant and most frequently detected perfluorinated compounds (PFCs) in home dust 29, can induce glutathione S-transferase Pi (GSTP) aberrant methylation 30. Heavy metals, such as arsenic (As), can differentially alter DNA methylation status in specific genes of white blood cells and it to this mechanism that Arsenic’s toxicity may be attributed 31. Polycyclic aromatic hydrocarbons (PAHs) have been found to increase asthma risk in children, which has been related to deviating methylation of the acyl-CoA synthetase long-chain family member 3 (ACSL3) and Interferon gamma (IFNG) 23233. Dichlorodiphenyltrichloroethane (DDT) has a long history as an ED. The compound was once used randomly as an insecticide in the agricultural sectors and it has been found to cause hypomethylation in the young hypothalamus of male rats 34. Vinclozolin (Vz), a fungicide, exerts antiandrogenic activity, and by modifying the methylation status in the sperm of animals' first generation it induces adult-beginning diseases that can last, trans-generationally, until the F3 generation 535.

Many genes are known to be hormonally regulated, including the family of kallikrein-related peptidases (KLKs) 3637, such as KLK1, KLK2 38, KLK5, KLK6, KLK7, KLK8, KLK9 39, KLK10 40, KLK11, and KLK12 41. Many of these genes are also important cancer and/or leukemia biomarkers 4243444546474849. Other genes that are similarly regulated include members of the BCL2 family 5051, such as BCL2 52, BAX 5354, and BCL2L12 5556575859, which has been shown to produce many alternative splice variants, using classical molecular cloning techniques and next-generation sequencing (NGS) 6061. NGS is a very powerful methodology that can reveal the depth of genomes and transcriptomes 62. Epigenetically regulated transcription factors 63 such as HIF1 64 and STAT3 65, as well as other genes, including DDC 6667, PA28γ 68, PIK3CA 69, NBS1 70, and PD-L1 71.