Endocrine disruptors of sex hormone activities

Abstract

Sex hormones, such as androgens, estrogens and progestins are naturally occurring compounds that tightly regulate endocrine systems in a variety of living organisms. Uncontrolled environmental exposure to these hormones or their biological and synthetic mimetics has been widely documented. Furthermore, water contaminants penetrate soil to affect flora, fauna and ultimately humans. Because endocrine systems evolved to respond to very small changes in hormone levels, the low levels found in the environment cannot be ignored. The combined actions of sex hormones with glucocorticoids and other nuclear receptors disruptors creates additional level of complexity including the newly described "dynamic assisted loading" mechanism. We reviewed the extensive literature pertaining to world-wide detection of these disruptors and created a detailed Table on the development and current status of methods used for their analysis.

Keywords: Biological activity; Endocrine disrupting compounds; Hormones; Soil; Water.

Figure 1:

Sex hormones activate cellular receptors in the large family of nuclear receptors (NRs), some of which reside in the cytoplasm (such as AR and GR) while others are predominantly nuclear. Irrespective to their location, binding to a ligand (hormone or an EDC mimicking a hormone) induces a rapid and transient exclusive localization in the nucleus. Once in the nucleus, these NRs become ligand-regulated TFs that bind their respective DNA sequences and interact with variety of chromatin remodelers to influence chromatin state to open or close sites needed for their own actions as well as facilitating the binding of other TFs. Thus, activated NRs can assist each other in binding to DNA sites by a mechanism called “dynamic-assisted loading” and thus substantially modify the final transcriptional outcome (Goldstein and Hager, 2018; Madsen et al., 2014; Miranda et al., 2013b; Swinstead et al., 2016b). H1 and H2 – Hormone 1and Hormone 2 NR1 and NR2 – Nuclear Receptors 1 and 2. NR1 depicts receptors which reside in the cytoplasm and translocate to the nucleus upon binding to a ligand (GR, AR, and aryl hydrocarbon receptor, AhR are exclusively cytoplasmic in the absence of the ligand). However, any NR can function as an initiating TF and assist the loading of other NRs to their usual or a novel regulatory site. HSP70 and HSP90 – components of heat shock protein complexes that bind AR, AhR and GR to maintain them in the cytoplasm by conformation that hides their nuclear localization sites. Once a ligand binds to these receptors, the chaperone complex dissociates, allowing H/NR complex to translocate to the nucleus where they become TFs and bind DNA. Chromatin remodelers complex – interact with TFs and reposition nucleosomes to allow TFs to access specific sites on DNA. Chromatin remodelers contain multiple proteins that are subdivided into four major families of: SWI/SNF, ISWI, CHD, and INO80 (Clapier and Cairns, 2009).