Despite being banned from production for decades, polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health. This is due to not only the continued release of legacy PCBs from PCB-containing equipment and materials manufactured prior to the ban on PCB production, but also the inadvertent production of PCBs as byproducts of contemporary pigment and dye production. Evidence from human and animal studies clearly identifies developmental neurotoxicity as a primary endpoint of concern associated with PCB exposures. However, the relative role(s) of specific PCB congeners in mediating the adverse effects of PCBs on the developing nervous system, and the mechanism(s) by which PCBs disrupt typical neurodevelopment remain outstanding questions. New questions are also emerging regarding the potential developmental neurotoxicity of lower chlorinated PCBs that were not present in the legacy commercial PCB mixtures, but constitute a significant proportion of contemporary human PCB exposures. Here, we review behavioral and mechanistic data obtained from experimental models as well as recent epidemiological studies that suggest the non-dioxin-like (NDL) PCBs are primarily responsible for the developmental neurotoxicity associated with PCBs. We also discuss emerging data demonstrating the potential for non-legacy, lower chlorinated PCBs to cause adverse neurodevelopmental outcomes. Molecular targets, the relevance of PCB interactions with these targets to neurodevelopmental disorders, and critical data gaps are addressed as well.

Increasing evidence indicates that the central nervous system (CNS) is a target of air pollution. We previously reported that postnatal exposure of mice to concentrated ambient ultrafine particles (UFP; ≤100 nm) via the University of Rochester HUCAPS system during a critical developmental window of CNS development, equivalent to human 3rd trimester, produced male-predominant neuropathological and behavioral characteristics common to multiple neurodevelopmental disorders, including autism spectrum disorder (ASD), in humans. The current study sought to determine whether vulnerability to fine (≤2.5 μm) and UFP air pollution exposure extends to embryonic periods of brain development in mice, equivalent to human 1st and 2nd trimesters. Pregnant mice were exposed 6 h/day from gestational days (GDs) 0.5–16.5 using the New York University VACES system to concentrated ambient fine/ultrafine particles at an average concentration of 92.69 μg/m³ over the course of the exposure period. At postnatal days (PNDs) 11–15, neuropathological consequences were characterized. Gestational air pollution exposures produced ventriculomegaly, increased corpus callosum (CC) area and reduced hippocampal area in both sexes. Both sexes demonstrated CC hypermyelination and increased microglial activation and reduced total CC microglia number. Analyses of iron deposition as a critical component of myelination revealed increased iron deposition in the CC of exposed female offspring, but not in males. These findings demonstrate that vulnerability of the brain to air pollution extends to gestation and produces features of several neurodevelopmental disorders in both sexes. Further, they highlight the importance of the commonalities of components of particulate matter exposures as a source of neurotoxicity and common CNS alterations.