Transgenerational transmission of prenatal maternal stress across three generations of male progeny alters inflammatory stress markers in reproductive tissues

Prenatal maternal stress may lead to adverse pregnancy outcomes such as preterm birth and low birth weight. Our team has demonstrated in multiple rat models that prenatal maternal stress modifies the expression of inflammatory and stress regulators in the uterus and that this is transgenerationally passed over multiple generations through the female progeny. In this study, we investigated if male progeny exposed to ancestral prenatal maternal stress could also transmit changes to cause fetal programming of reproductive organs, leading to adverse pregnancy outcomes. We created a paternal transgenerational prenatal stress rat model. Dams (F0) were exposed to chronic variable stress during pregnancy, and their F1 male offspring stressed in utero were bred with control females for two generations. Gestational lengths and litter sizes were unchanged. Elevated gene expression of pro-inflammatory molecules in the uteri of F2 and F3 offspring was observed. Uterine expression of stress markers in the F2 and F3 females also increased even though plasma corticosterone levels were unchanged. Changes in the testicular expression of inflammatory and stress markers were also transmitted through the paternal lineage. These changes, however, tended to bear anti-inflammatory and adaptive functions, indicating compensatory mechanisms at play. These results demonstrate that fetal programming of uterine and testicular gene expression patterns can be transmitted through male progeny exposed to prenatal maternal stress.