The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

Abstract

Adversity experienced during gestation is a predictor of lifetime neuropsychiatric disease susceptibility. Specifically, maternal stress during pregnancy predisposes offspring to sex-biased neurodevelopmental disorders, including schizophrenia, attention deficit/hyperactivity disorder, and autism spectrum disorders. Animal models have demonstrated disease-relevant endophenotypes in prenatally stressed offspring and have provided unique insight into potential programmatic mechanisms. The placenta has a critical role in the deleterious and sex-specific effects of maternal stress and other fetal exposures on the developing brain. Stress-induced perturbations of the maternal milieu are conveyed to the embryo via the placenta, the maternal-fetal intermediary responsible for maintaining intrauterine homeostasis. Disruption of vital placental functions can have a significant impact on fetal development, including the brain, outcomes that are largely sex-specific. Here we review the novel involvement of the placenta in the transmission of the maternal adverse environment and effects on the developing brain.

Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood

“…In the third trimester, the time point at which the samples for analyses here were drawn, IL-8 is up-regulated via activation of the prokineticin1 receptor (PKR1) for endothelial cell chemotaxis and proliferation (48). In animal models, increased glucocorticoid exposure early in the third trimester has been reported to inhibit the expression of the PKR1 ligand, prokineticin1 (PK1), resulting in decreased placental vascularization (50) and, consequently, deficits in fetal neurodevelopment (51). Furthermore, the receptor for IL-8, CXCR2, is present in the human fetal brain and plays a role in synaptogenesis (52).…”

Sex differences in the gut microbiome–brain axis across the lifespan

“…As the developing fetus receives all nutrients from the maternal circulation, and as the metabolic demand of male and female fetuses differs during gestation, the capacity of the maternal gut microbiome to mediate maternal energy balance and nutritional status may exhibit significant sex-specific effects on development [75,76]. Emerging evidence suggests that the maternal gut microbiome orchestrates nutrient and metabolite availability in a temporal-specific manner [77].…”

SExual Epigenetic Dimorphism in The Human Placenta: Implications for Susceptibility During The Prenatal Period

“…For instance, key differences in chromatin structure have been observed between male and female placentas, suggesting that there is a role for epigenetic regulation in placental sexual dimorphism [12,21]. Understanding epigenetic regulation in the placenta is important given the modifiability of its epigenome in response to prenatal stressors, and its role as a mediator of the developmental origins of health and disease [2,20,21,28]. Additionally, because certain epigenomic markers are stable over time [29], it is possible that changes to the fetal placenta methylome explain the sex-based differences in later-life disease risks.…”