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

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-, β-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 µM p,p′DDT on cAMP production and on β-arrestin 2 recruitment were measured using bioluminescence and time-resolved resonance energy transfer technology. The impact of 100 µM of p,p′DDT on steroid secretion was analysed in murine Leydig tumor cell line (mLTC-1). In cAMP assays, 100 µM 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 µM p,p′DDT decreased the hCG- and hLH-promoted β-arrestin 2 recruitment down to 14.2 and 26.6%, respectively. Moreover, 100 µM 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.