IUGR disrupts the PPARγ-Setd8-H4K20me1 and Wnt signaling pathways in the juvenile rat hippocampus

•Intrauterine growth restriction programs neurodevelopmental impairment and long-term neurological morbidities.•We use a rat model to test the effects of IUGR on two developmentally important pathways; PPARγ-Setd8-H4K20me1 and Wnt signaling.•IUGR reduces mRNA and protein components of both pathways as well as mRNA of final target gene Axin2.•IUGR programming of neurodevelopmental impairment likely involves disruption to the PPARγ-Setd8-H4K20me1 and Wnt signaling pathways.

Intrauterine growth restriction (IUGR) programs neurodevelopmental impairment and long-term neurological morbidities. Neurological morbidities in IUGR infants are correlated with changes hippocampal volume. We previously demonstrated that IUGR alters hippocampal cellular composition in both neonatal and juvenile rat pups in association with altered hippocampal gene expression and epigenetic determinants. PPARγ signaling is important for neurodevelopment as well as epigenetic integrity in the brain via the PPARγ-Setd8-H4K20me1 axis and Wnt signaling. We hypothesized that IUGR would decrease expression of PPARγ, Setd8, and H4K20me1 in juvenile rat hippocampus. We further hypothesized that reduced PPARγ-Setd8-H4K20me1 would be associated with reduced Wnt signaling genes Wnt3a and β-catenin, and wnt target gene Axin2. To test our hypothesis we used a rat model of uteroplacental insufficiency-induced IUGR. We demonstrated that PPARγ localizes to oligodendrocytes, neurons and astrocytes within the juvenile rat hippocampus. We also demonstrated that IUGR reduces levels of PPARγ, Setd8 and H4K20me1 in male and female juvenile rat hippocampus in conjunction with reduced Wnt signaling components in only male rats. We speculate that reduced PPARγ and Wnt signaling may contribute to altered hippocampal cellular composition which, in turn, may contribute to impaired neurodevelopment and subsequent neurocognitive impairment in IUGR offspring.