Gestational exposure to ziram disrupts rat fetal Leydig cell development

Ziram is an endocrine disruptor and may cause birth abnormality of the male reproductive system. However, the effects of ziram on fetal Leydig cell (FLC) development are still unknown. The objective of the present study was to determine the endocrine-disrupting effect of ziram on rat FLC development after gestational exposure. Pregnant Sprague Dawley dams were randomly divided into 5 groups and were gavaged with 0 (corn oil, the control), 1, 2, 4, or 8 mg/kg ziram from gestational day 12 (GD12) to GD21. FLC development was evaluated by measuring serum testosterone, FLC number and distribution, and the expression levels of Leydig and Sertoli cell genes. Ziram significantly increased serum testosterone level at 1 mg/kg (1.350 ± 0.099 ng/ml vs. 0.989 ± 0.106 ng/ml in the control), while it remarkably lowered it at 8 mg/kg (0.598 ± 0.086 ng/ml). Quantitative immunohistochemical staining showed that ziram increased FLC number via stimulating cell proliferation at 1 mg/kg and lowered it via inhibiting its proliferation at 8 mg/kg without affecting Sertoli cell number. Further study demonstrated that the expression of Nr5a1, Lhcgr, Scarb1, Star, Cyp11a1, and Cyp17a1 genes and proteins in the testis was upregulated at 1 mg/kg and the expression of Leydig (Nr5a1, Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1, and Insl3) and Sertoli cell (Fshr, Hsd17b3, Dhh, Amh, and Sox9) genes and proteins was downregulated by ziram at 8 mg/kg. In conclusion, ziram had biphasic effects on FLC development with low dose to increase FLC number and function and high dose to decrease them.