Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study

Valentine Suteau; Lorena Zuzic; Ditlev Høj Hansen; Lisbeth R. Kjølbye; Paul Sibilia; Louis Gourdin; Claire Briet; Mickaël Thomas; Eric Bourdeaud; Hélène Tricoire-Leignel; Birgit Schiøtt; Pascal Carato; Patrice Rodien; Mathilde Munier

doi:10.1016/j.jhazmat.2024.135619

Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study

Valentine Suteau, Lorena Zuzic, Ditlev Høj Hansen, Lisbeth R. Kjølbye, Paul Sibilia, Louis Gourdin, Claire Briet, Mickaël Thomas, Eric Bourdeaud, Hélène Tricoire-Leignel, Birgit Schiøtt, Pascal Carato, Patrice Rodien, Mathilde Munier^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.

Original language	English
Article number	135619
Journal	Journal of Hazardous Materials
Volume	479
ISSN	0304-3894
DOIs	https://doi.org/10.1016/j.jhazmat.2024.135619
Publication status	Published - 5 Nov 2024

Keywords

Endocrine disruptors - Bisphenol A - FSH/FSH receptor signaling - Molecular docking and dynamics simulations - Health risk

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10.1016/j.jhazmat.2024.135619

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Suteau, V., Zuzic, L., Hansen, D. H., Kjølbye, L. R., Sibilia, P., Gourdin, L., Briet, C., Thomas, M., Bourdeaud, E., Tricoire-Leignel, H., Schiøtt, B., Carato, P., Rodien, P., & Munier, M. (2024). Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study. Journal of Hazardous Materials, 479, Article 135619. https://doi.org/10.1016/j.jhazmat.2024.135619

@article{4cab214923ef43cca016a8829652cb13,

title = "Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study",

abstract = "Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.",

keywords = "Endocrine disruptors - Bisphenol A - FSH/FSH receptor signaling - Molecular docking and dynamics simulations - Health risk",

author = "Valentine Suteau and Lorena Zuzic and Hansen, {Ditlev H{\o}j} and Kj{\o}lbye, {Lisbeth R.} and Paul Sibilia and Louis Gourdin and Claire Briet and Micka{\"e}l Thomas and Eric Bourdeaud and H{\'e}l{\`e}ne Tricoire-Leignel and Birgit Schi{\o}tt and Pascal Carato and Patrice Rodien and Mathilde Munier",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = nov,

day = "5",

doi = "10.1016/j.jhazmat.2024.135619",

language = "English",

volume = "479",

journal = "Journal of Hazardous Materials",

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Suteau, V, Zuzic, L, Hansen, DH, Kjølbye, LR, Sibilia, P, Gourdin, L, Briet, C, Thomas, M, Bourdeaud, E, Tricoire-Leignel, H, Schiøtt, B, Carato, P, Rodien, P & Munier, M 2024, 'Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study', Journal of Hazardous Materials, vol. 479, 135619. https://doi.org/10.1016/j.jhazmat.2024.135619

Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study. / Suteau, Valentine; Zuzic, Lorena; Hansen, Ditlev Høj et al.
In: Journal of Hazardous Materials, Vol. 479, 135619, 05.11.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor

T2 - An interdisciplinary study

AU - Suteau, Valentine

AU - Zuzic, Lorena

AU - Hansen, Ditlev Høj

AU - Kjølbye, Lisbeth R.

AU - Sibilia, Paul

AU - Gourdin, Louis

AU - Briet, Claire

AU - Thomas, Mickaël

AU - Bourdeaud, Eric

AU - Tricoire-Leignel, Hélène

AU - Schiøtt, Birgit

AU - Carato, Pascal

AU - Rodien, Patrice

AU - Munier, Mathilde

PY - 2024/11/5

Y1 - 2024/11/5

N2 - Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.

AB - Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.

KW - Endocrine disruptors - Bisphenol A - FSH/FSH receptor signaling - Molecular docking and dynamics simulations - Health risk

UR - http://www.scopus.com/inward/record.url?scp=85202765025&partnerID=8YFLogxK

U2 - 10.1016/j.jhazmat.2024.135619

DO - 10.1016/j.jhazmat.2024.135619

M3 - Journal article

C2 - 39217935

AN - SCOPUS:85202765025

SN - 0304-3894

VL - 479

JO - Journal of Hazardous Materials

JF - Journal of Hazardous Materials

M1 - 135619

ER -

Effects and risk assessment of halogenated bisphenol A derivatives on human follicle stimulating hormone receptor: An interdisciplinary study

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