Oral or Poster Presentation
Plenary Session - Life Course Effects of Maternal Diabetes
Introduction: Prenatal synthetic glucocorticoids(sGC) are administered to women with threatened preterm labour. However, sGC treatment has been associated with poor neurodevelopmental outcomes in multiple species. Indeed, sGC exposure has been shown to impact neuroendocrine function, behaviour and brain transcriptome profiles for three generations following paternal transmission in guinea pigs. MicroRNA(miRNA) in the male germline are key regulatory factors that may underlie transgenerational transmission. We hypothesized that prenatal sGC exposure(F0 pregnancy) modifies miRNA expression in adult male germline cells across three generations.
Methods: Pregnant F0 guinea pigs were injected with three courses of a clinically relevant dose of betamethasone(BETA) or saline(Ctrl). Male offspring(F1) were mated with naïve females to produce two further generations. Once successfully mated to produce next generation, adult male offspring(F1-3) were euthanized. MiRNA-microarray was performed in germ cells isolated from F1-3 males' testes(n=6/group). Data was processed by TAC2.0 and R. Log2-fold change(FC) >+-1.5, FDR corrected p<0.05 was considered significant.
Results: Maternal(F0) BETA treatment resulted in differential expression of 216, 147, 232 miRNAs in germ cells derived from F1-3 compared to Ctrl, respectively. Overall, different sets of miRNAs were affected in each generation; primarily down-regulated in F1, both directions in F2, and up-regulated in F3 male germ cells. However, a few miRNA showed the same pattern of altered expression in germ cells from all three generations after sGC, such as miR-125b(FC(F1-3)=-3.94, -3.66, -2.87). The affected miRNA were shown to be associated with neurodevelopmental functions.
Conclusion: Prenatal sGC exposure(F0) modifies the miRNA expression in male germ cells across multiple generations(F1-3). While the overall miRNA profiles are different in each generation, some changes of specific miRNA are common in F1-3. These miRNA changes may be involved in the transgenerational effects of prenatal sGC on neuroendocrine function and behaviours described previously. Our findings provide new perspectives on the mechanisms of transgenerational transmission.