The role of miRNAs in regulating the effect of prenatal cadmium exposure on ovarian granulosa cells in a transgenerational manner in female rats.

Cadmium (Cd) is known to affect ovarian granulosa cells (GCs), but no information on the transgenerational effects of Cd on GCs. In this study, pregnant Sprague-Dawley (SD) rats were orally dosed with Cd from gestation day 1 until birth. F1 or F2 female rats were mated with untreated males to produce the F2 or F3 generation. In the F1 generation, apoptotic cell bodies were observed in the Cd-treated group but not in the F2 generation. Moreover, significant changes in B-cell lymphoma 2 (Bcl2) expression were observed in both generations. Additionally, the expression of microRNAs (miRNAs) was significantly changed based on microarray analysis. Specifically, miR-16-5p and miR-181b-5p were upregulated in F1 and F2 rats, while miR-92a-2-5p demonstrated different expression patterns between the two generations. In F3 generation, miR-16-5p and miR-92a-2-5p were down-regulated. Further, another experiment was used to show that miR-16-5p and miR-92a-2-5p regulated the Bcl2-induced apoptotic effect of Cd on GCs by the Human ovarian GC tumor line (COV434 cell line) miRNA-knockdown model Overall, the results indicate that prenatal Cd exposure has epigenetic transgenerational effect on GCs, Moreover, the underlying mechanism may involve interference with miR-16-5p and miR-92a-2-5p-mediated regulation of Bcl2 genes in offspring.