New Insights into Prenatal NO2 Exposure and Behavioral Abnormalities in Male Offspring: Disturbed Serotonin Metabolism and Delayed Oligodendrocyte Development

Epidemiological studies show that prenatal exposure to nitrogen dioxide (NO2) might cause behavioral abnormalities in childhood. However, toxicological mechanisms for such effects remain unclear, and it is still difficult to define adverse outcome pathways linking exposures to behavioral phenotypes. In this study, by exposing pregnant mice to NO2 (2.5 ppm, 5 h/day) throughout gestation, we provided the first experimental evidence that prenatal NO2 exposure did cause anxiety-and depression-like behaviors in weaning male offspring but not females. Specifically, the behavioral abnormalities were associated with abnormal myelination and the alterations attributed to the delayed oligodendrocyte (OL) development in the fetus and the early stage after birth. The expression of platelet-derived growth factor receptor alpha (Pdgfr-alpha) and Olig2 significantly decreased in the NO2 group at E13.5 and E15.5, and the expression of Olig2, adenomatous polyposis coli colon (Cc1), and myelin basic protein (Mbp) was reduced in offspring at PNDs 1, 7, and 21. We performed the targeted metabolomic analysis of neurotransmitters in the placenta and found that prenatal exposure to NO2 disturbed the metabolism of placental neurotransmitters. Serotonin (5-HT) was transferred from the placenta to the fetus at E10.5, and its accumulation in the fetal forebrain might affect oligodendrocyte progenitor cell (OPC) differentiation and OL maturation and eventually be involved in behavioral abnormalities. Our findings provide new insights into the association between prenatal NO2 exposure with anxiety-and depression-like behaviors in male offspring.