Maternal genetic intergenerational and transgenerational effects on hormone synthesis in ovarian granulosa cells of offspring exposed to cadmium during pregnancy

This study aimed to investigate the maternally inherited intergenerational and transgenerational effects of cadmium (Cd) exposure on steroid hormone synthesis in the ovarian granulosa cells (GCs) of offspring rats. F1 rats were obtained by mating adult female Sprague-Dawley rats with healthy adult male rats and were exposed to 0, 0.5, 2.0, and 8.0 mg/kg CdCl2 during pregnancy. The adult female rats (PND 56) were mated with healthy adult male rats to produce F2 and F3 rats. The serum progesterone (Pg) and estradiol (E2) levels of the F2 adult female rats were decreased, while those of F3 rats were significantly increased. Moreover, hormone synthesisrelated genes had different expression patterns in the F2 and F3 generations. F2 and F3 rat ovarian GCs exhibited altered miRNA expression profiles and DNA methylation patterns. Validation of miRNAs that regulate hormone synthesis-related genes in the cAMP/PKA signaling pathway suggested that miR-124-3p was downregulated in F2 and F3 rats, while miR-133a-5p and miR-150-5p were upregulated in F2 rats and downregulated in F3 rats. In summary, 1) there are maternal genetic intergenerational (GCs hormone synthesis disorder) and transgenerational (GCs hormone synthesis function repair change) effects on hormone synthesis function changes in offspring GCs induced by Cd exposure during pregnancy. 2) Changes in miRNAs and DNA methylation modifications associated with the genetic effects of altered hormone synthesis function in offspring GCs induced by Cd exposure during pregnancy are important. 3) Under the current environmental level of Cd exposure, the possible risk of maternal genetic intergenerational and transgenerational effects of offspring ovarian toxicity should be strongly considered.