Sex-Specific Differences of Steroid Receptors Following Exposure to Environmentally Relevant Concentrations of Phenothiazine in Fundulus heteroclitus

Abstract

Agricultural runoff and industrial discharge are known to contaminate ground and surface waters and are not typically removed during water purification. These compounds may have significant effects on biological systems through the disruption of normal endocrine function. This study aims to determine the sex specific effects of phenothiazine (PTZ), a potential endocrine disruptor, on markers for endocrine disruption and stress in Fundulus heteroclitus. The following steroid hormone receptors were assessed: glucocorticoid receptor (GR), androgen receptor (AR), progesterone receptor (PR), estrogen related receptor alpha (ERα), estrogen receptor beta A (ERβA), and estrogen receptor beta B (ERβB). Phenothiazine was detected at levels between 1–2ppm via gas chromatography‐mass spectrophotometry (GC‐MS) in river water sampling conducted in southern Connecticut, but the biological impact of the compound is unknown. Phenothiazine has been used previously as an antipsychotic medication, as well as, industrially in plastics to add softness and flexibility. To assess the impact of phenothiazine, female and male fish were exposed to environmentally relevant concentrations of phenothiazine for one week and sacrificed. Brain, liver, and gonad tissues were removed and pooled from each treatment group. Quantitative PCR (qPCR) was conducted on tissues and analysis showed significant changes in mRNA expression and both a sex‐specific and tissue specific response. There were no changes in the testis and the female liver. In male brain there was a decrease in GR at 1ppm (p<0.05), and an increase in ERβB at 2ppm (p<0.01); in comparison to female brain which had an increase in PR (p< 0.01), AR (p<0.05), ERα (p< 0.0001) and ERβB (p<0.05). In male liver there was an upregulation in GR (p<0.05), and AR (p<0.05) mRNA expression and a down regulation of ERβB (p<0.0001). Lastly, within the ovary there is an increase in AR (p<0.05) and ERβA (p< 0.01) mRNA expression and a decrease in GR (p<0.05) mRNA expression. These findings indicate that phenothiazine may alter endocrine function through the steroid hormone receptors. Collectively, these tissue specific results demonstrate how phenothiazine disrupts normal fish physiology. Additionally, serum cortisol levels were assayed via enzyme linked immunosorbent assay (ELISA) and no significant changes in cortisol levels following phenothiazine treatment were observed. Support or Funding Information Connecticut Community Foundation, Quinnipiac River Fund This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Expedition of sulfur‐containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update

“…239,240 These drugs belong to a class of dopamine receptors antagonists, which are used in the treatment of several mental illnesses. 241 Literature supports that these dopamine receptors are expressed in various cancer cells and hence can be a potential target for anticancer therapy. 242,243 Thus, apart from their neuroleptic effects, this class of drugs exhibits multiple other actions such as, antiemetic, antimicrobial, 244 antihistaminic, antipruritic, analgesic, and antihelmintic.…”