Tetramethyl bisphenol A stimulates proliferation but inhibits fetal Leydig cell function in male rats by targeting estrogen receptor α after in utero exposure

Tetramethyl bisphenol A (TMBPA) is a widely used flame retardant. TMBPA has been a toxic to Leydig cells in puberty, but it remains unclear whether TMBPA has a similar inhibitor effect on fetal Leydig cells (FLCs). This study reported morphological and functional alterations of FLCs in the testes of male offspring at birth after in utero exposure to TMBPA. Pregnant Sprague Dawley rats were dosed via continuous gavage of TMBPA (0, 10, 50, and 200 mg/kg/day) from gestational day 14 to 21. TMBPA markedly raised serum total testosterone level, testicular volume, and FLC number of male offspring at 200 mg/kg dose. The up-regulation of Insl3, Star, and Cyp11a1 mRNAs was observed after 200 mg/kg TMBPA exposure. After normalization to the number of FLCs, TMBPA significantly reduced Lhcgr and Hsd3b1 expressions at 10 mg/kg, and Cyp17a1 at 200 mg/kg paralleling with their protein levels. TMBPA compromised the expression of Esr1, while increased the expression of Cdk2 and Cdk4 as well as their protein levels. TMBPA particularly increased the phosphorylation of AKT1 and AKT2 at 200 mg/kg. In conclusion, the present study suggests that TMBPA may promote FLC proliferation via ESR1-CDK2/4-AKT pathway, while inhibits the function of FLCs by reducing steroidogenic enzyme activity.