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In vitro effects of the endocrine disruptor p,p' DDT on human choriogonadotropin/luteinizing hormone receptor signalling

Mathilde Munier 1, 2, * Mohammed Ayoub 3, 4 Valentine Suteau 1, 2 Louis Gourdin 1, 2 Daniel Henrion 1 Eric Reiter 4, 5 Patrice Rodien 1, 2
* Auteur correspondant
5 MUSCA - Dynamiques de populations multi-échelles pour des systèmes physiologiques
Inria Saclay - Ile de France, PRC - Physiologie de la reproduction et des comportements [Nouzilly], MaIAGE - Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas]
Abstract : Dichlorodiphenyltrichloroethane (p,p ' DDT) is an endocrine-disrupting chemical (EDC). Several studies showed an association between p,p ' DDT exposure and reprotoxic effects. We showed that p,p ' DDT was a positive allosteric modulator of human follitropin receptor (FSHR). In contrast, we demonstrated that p,p ' DDT decreased the cyclic AMP (cAMP) production induced by human choriogonadotropin (hCG). This study evaluated further the effects of p,p ' DDT on Gs-, beta-arrestin 2- and steroidogenesis pathways induced by hCG or luteinizing hormone (LH). We used Chinese hamster ovary cells line stably expressing hCG/LHR. The effects of 10-100 mu M p,p ' DDT on cAMP production and on beta-arrestin 2 recruitment were measured using bioluminescence and time-resolved resonance energy transfer technology. The impact of 100 mu M of p,p ' DDT on steroid secretion was analysed in murine Leydig tumor cell line (mLTC-1). In cAMP assays, 100 mu M p,p ' DDT increased the EC50 by more than 300% and reduced the maximum response of the hCG/LHR to hCG and hLH by 30%. This inhibitory effect was also found in human granulosa cells line and in mLTC-1 cells. Likewise, 100 mu M p,p ' DDT decreased the hCG- and hLH-promoted beta-arrestin 2 recruitment down to 14.2 and 26.6%, respectively. Moreover, 100 mu M p,p ' DDT decreased by 30 and 47% the progesterone secretion induced by hCG or hLH, respectively, without affecting testosterone secretion. This negative effect of p,p'DDT was independent of cytotoxicity. p,p ' DDT acted as a negative allosteric modulator of the hCG/LHR signalling. This emphasizes the importance of analyzing all receptor-downstream pathways to fully understand the deleterious effects of EDC on human health.
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https://hal.univ-angers.fr/hal-03164658
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Soumis le : mercredi 10 mars 2021 - 10:05:10
Dernière modification le : mardi 3 mai 2022 - 14:40:13

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Mathilde Munier, Mohammed Ayoub, Valentine Suteau, Louis Gourdin, Daniel Henrion, et al.. In vitro effects of the endocrine disruptor p,p' DDT on human choriogonadotropin/luteinizing hormone receptor signalling. Archives of Toxicology, Springer Verlag, 2021, 95 (5), pp.1671-1681. ⟨10.1007/s00204-021-03007-1⟩. ⟨hal-03164658⟩

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