Maternal diet disrupts the placenta-brain axis in a sex-specific manner

Abstract

SUMMARYHigh maternal weight is associated with a number of detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression, and communicative disorders (e.g. autism spectrum disorders)1–4. Despite widespread acknowledgement of sex-biases in the prevalence, incidence, and age of onset of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we use a mouse model to demonstrate how maternal high-fat diet causes perinatal inflammation that influences sex-specific behavioral outcomes in offspring. In male high-fat diet offspring, increased macrophage toll like receptor 4 signaling results in excess phagocytosis of serotonin neurons in the developing dorsal raphe nucleus, decreasing serotonin bioavailability in the fetal and adult brain. Bulk sequencing from a large cohort of matched first trimester human fetal brain, placenta, and maternal decidua samples reveals sex-specific transcriptome-wide changes in placenta and brain tissue. Further, we find that fetal brain serotonin is significantly negatively correlated with maternal triglyceride accumulation (a proxy for dietary fat content) in male pregnancies only. These findings uncover a fundamental mechanism through which maternal diet may increase offspring susceptibility for neuropsychiatric disorder development.