Endocrine Abstracts

Numerous epidemiological studies link exposure to Bisphenol A (BPA) to reproductive function anomalies. Our team recently showed that BPA inhibits the action of Follicle Stimulating Hormone (FSH) on its receptor (FSHR). Water decontamination is achieved by chloration, which leads to the formation of chlorinated derivatives of Bisphenol A (Cl_XBPA), that may be found in natural environments and biological liquids or organs. In the presence of bromine, the formation of brominated derivatives of BPA (Br_XBPA) is also expected. One to four chlore or bromine atoms may link to the BPA molecule. Our work aimed at determine precisely the effects of Cl_XBPA and Br_xBPA on the activity of the FSHR. We used a CHO cell line, which endogenously and stably express the human FSHR. The activity of the receptor is assessed by measuring the cyclic AMP (cAMP) production. Cl_XBPA compounds were synthesized with sulfuryl chloride, and Br_XBPA with Br₂, and purified by LC/MS/MS. First, we verified the absence of cell toxicity of the compounds by an MTT test. BPA at the concentration of 10⁻⁷ M reduces the production of cAMP stimulated by FSH by roughly 40%. Likewise, Cl_XBPA diminish by 30% the response of the FSHR to FSH, without altering the basal activity of the receptor, suggesting a negative allosteric effect. Cl₄BPA (10⁻⁸ M) is the most powerful negative modulator of the FSH response, followed by Cl₃BPA (10⁻⁷ M) and Cl₂BPAs and Cl₁BPA (10⁻⁵ M). In the same way, Br_XBPA have an inhibiting effect on response to FSH, with up to 30% reduction. They have no effect on the basal activity of the receptor, then again suggesting a negative allosteric effect. These results show for the first time that, like BPA, halogenous derivatives of BPA can be considered as endocrine disruptors and may have reprotoxic effects that need better characterization.