Pregnancy and lactation differentially modify the transcriptional regulation of steroidogenic enzymes through DNA methylation mechanisms in the hippocampus of aged rats

• Pregnancy with lactation increase the expression of hippocampal steroidogenic genes.
• Pregnancy without lactation increase only 5αR-1 and P450scc gene expression.
• Pregnancy without lactation decrease the transcription of P450arom and P450(11β)-2.
• These changes were associated with modifications in the promoter methylation states.

In the present study, we examined the mRNA expression and DNA methylation state of steroidogenic enzymes in the hippocampus of young adult (90-days-old) and middle-aged (450-days-old) nulliparous rats, and middle-aged multiparous rats subjected to three pregnancies with and without lactation. Aging decreased the mRNA levels of steroidogenic-related genes, while pregnancy and lactation significantly reduced the effect of aging, maintaining high expression levels of cytochrome P450 side-chain cleavage (P450scc), steroid 5α-reductase-1 (5αR-1), cytochrome P450arom (P450arom) and aldosterone synthase (P450(11β)-2). In addition, pregnancy and lactation diminished the methylation state of the 5αR-1 promoter and increased the transcription of brain-derived neurotrophic factor, synaptophysin and spinophilin. Pregnancy without lactation increased P450scc and 5αR-1 gene expression and decreased the methylation of their promoters. We concluded that the age-related decrease in the mRNA expression of steroidogenic enzymes is differentially attenuated by pregnancy and lactation in the rat hippocampus and that differential methylation mechanisms could be involved.