Endocrine Disruptors Acting on Estrogen and Androgen Pathways Cause Reproductive Disorders through Multiple Mechanisms: A Review

Abstract

Increasing contamination of the environment by toxic compounds such as endocrine disrupting chemicals (EDCs) is one of the major causes of reproductive defects in both sexes. Estrogen/androgen pathways are of utmost importance in gonadal development, determination of secondary sex characteristics and gametogenesis. Most of the EDCs mediate their action through respective receptors and/or downstream signaling. The purpose of this review is to highlight the mechanism by which EDCs can trigger antagonistic or agonistic response, acting through estrogen/androgen receptors causing reproductive defects that lead to infertility. In vitro, in vivo and in silico studies focusing on the impact of EDCs on estrogen/androgen pathways and related proteins published in the last decade were considered for the review. PUBMED and PUBCHEM were used for literature search. EDCs can bind to estrogen receptors (ERα and ERβ) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.

Keywords: androgens; endocrine disrupting chemicals; estrogens; female; gonadal steroid hormones; human; infertility; male; mammals; reproduction.

Figure 1

Schematic presentation of the arrangement of domains in estrogen receptors (ER) alpha and beta. N: Amino Terminal, C: Carboxyl Terminal, AF: Activation Function, DBD: DNA binding Domain, LBD: Ligand binding Domain, adapted from [54].

Figure 2

Schematic diagram showing activation of estrogen receptor alpha in both ligand dependent and independent ways. ERs can mediate transcription of target genes either by binding to estrogen response elements (ERE) or binding to other transcription factors such as SP1 and AP1 [55].

Figure 3

Schematic presentation of sequence of domains in androgen receptor. N: amino terminal, C: carboxyl end, AF 1: Activation function 1, NTD: N terminal Domain, DBD: DNA binding domain, LBD: Ligand Binding Domain.

Figure 4

Schematic diagram showing the activation of the androgen receptor in both genomic and non-genomic pathways (after [57]).

Figure 5

Possible mechanism adapted by bisphenol A (BPA) to cause antagonistic effects to disrupt normal signaling of estradiol via estrogen receptors.