Cadmium exposure during prenatal development causes progesterone disruptors in multiple generations via steroidogenic enzymes in rat ovarian granulosa cells

Exposure to the heavy metal cadmium (Cd) in the environment is linked to adverse health. To fully understand the adverse effects of this important endocrine-disrupting compound (EDC) requires studies that address multigenerational effects and epigenetic mechanisms. The present study orally dosed pregnant SD rats with Cd from gestation day 1 until birth. First filial generation (F1) female rats were mated with untreated males to generate the secondary filial generation (F2). Ovarian granulosa cells (OGCs) were collected at postnatal day (PND) 56 from both generations after prenatal Cd exposure, and hormone secretion examinations showed a progesterone disorder. Significant decreases in steroidogenic enzymes (steroidogenic acute regulatory protein (StAR) and P450 cholesterol side-chain cleavage enzyme (CYP11A1)) were observed in F1 and F2 rats. However, F1 and F2 rats had different patterns of mRNA and protein expression of steroidogenic factor 1 (SF-1). We also found that microRNAs were significantly changed using a microarray, and miR-10b-5p and miR-27a-3p were upregulated in F1 and F2 rats. The COV434 cell line microRNA-knockdown model showed that these two important microRNAs regulated the StAR-induced Cd effect on progesterone secretion. Overall, the results of this study indicate that prenatal Cd exposure causes cytotoxicity problems, progesterone disorder and microRNAs expression changed in a multigenerational manner. And progesterone disorder may interfere with the steroidogenic enzymes in offspring. The present study also revealed that environmental pollution produces multigenerational effects.