Neurodevelopmental disorders including autism and schizophrenia show strong sex biases in presentation, onset and treatment. Such disorders have been associated with fetal antecedents including maternal stress. The programming mechanisms through which stress contributes to disease development are not well understood; though likely involve a complex interaction between the maternal environment and effects on the placenta. We have identified a sensitive period of early gestation where maternal stress has sex-dependent epigenetic programming effects on offspring stress pathway neurodevelopment. Male offspring show increased stress sensitivity as adults in behavioral and physiological measures including tests assessing cognitive performance and stress coping strategies. These males also demonstrate physiological features of dysmasculinization including reduced testosterone levels, smaller testes, and a shorter anogenital distance supporting a disruption in normal perinatal masculinization. Mechanistically, we have found dramatic changes in the neonatal brain miRNA environment in response to early prenatal stress that is programmed by the neonatal testosterone surge. From these large bioinformatics data mining analyses, families of miRNA genes specific to the developing hypothalamus were identified. In addition to the brain, maternal stress so early in pregnancy likely influences placental programming. As the placenta is a sex-specific tissue, we identified a limited set of genes that consistently differ between the sexes across pregnancy, all of which are located on the sex chromosomes. Utilizing a proteomics approach, we have found a candidate placental glycosylation enzyme and its biochemical target proteins that are significantly altered by maternal stress in male tissue. Chromatin immunoprecipitation analyses support a direct mechanism whereby stress experience decreases the transcriptional activator mark histone H3K4me3 association with this gene, decreasing its expression. As protein glycosylation typically competes with phosphorylation events, such broad changes are likely to yield important outcomes in placenta function and nutrient support of the developing fetus following stress. These results may provide critical insight into the mechanisms contributing to sex biased disease vulnerability to prenatal stress during early pregnancy. Further, as many neurodevelopmental disorders have a sex bias in presentation, these studies may provide novel biomarkers predictive of at-risk pregnancies.
These studies were supported by funding from grants from the NIH MH087597 and MH091258