Prenatal exposure to PCBs in Cyp1a2 knock-out mice interferes with F1 fertility, impairs long-term potentiation, reduces acoustic startle and impairs conditioned freezing contextual memory with minimal transgenerational effects

Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three-coplanar/five-noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2(-/-)::Ahr(b1) C57BL6/J mice compared with wild-type mice (Ahr(b1) = high AHR affinity). Here we exposed gravid Cyp1a2(-/-)::Ahr(b1) mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F-1 and F-3 offspring (not F-2). PCB-exposed F-1 mice exhibited increased open-field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long-term potentiation with no change in spatial learning or memory. F-1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F-3 mice showed few effects. Gene expression changes were primarily in F-1 PCB males compared with wild-type males. There were minimal RNA and DNA methylation changes in the hippocampus from F-1 to F-3 with no clear relevance to the functional effects. F-0 PCB exposure during a period of rapid DNA de-/remethylation in a susceptible genotype produced clear F-1 effects with little evidence of transgenerational effects in the F-3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.