ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 P1001 | DOI: 10.1530/endoabs.63.P1001

Halogenous derivatives of Bisphenol A inhibit the human FSH receptor activity

Paul Sibilia1,2,3, Manon Doumas4, Louis Gourdin1,2,3,5, Claire Briet1,2,3,5, Pascal Carato4, Patrice Rodien1,2,3,5 & Mathilde Munier1,2,3,5

1Endocrinology Department, University Hospital of Angers, Angers, France; 2UMR CNRS 6214-INSERM 1083, University of Angers, Angers, France; 3MITOVASC Institute, University of Angers, Angers, France; 4IC2MP, CNRS 7285 – CIC INSERM 1402, Poitiers University, Poitiers, France; 5Reference Center for Rare Diseases of the Thyroid and Hormonal Receptors, University Hospital of Angers, Angers, France.

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 (ClXBPA), that may be found in natural environments and biological liquids or organs. In the presence of bromine, the formation of brominated derivatives of BPA (BrXBPA) 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 ClXBPA and BrxBPA 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. ClXBPA compounds were synthesized with sulfuryl chloride, and BrXBPA 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, ClXBPA 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, BrXBPA 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.

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