Cytochrome P450 Expression Influences Behavioral Responses to 3,3ʹ-Dichlorobiphenyl (PCB 11) in Juvenile Male and Female Mice Exposed Throughout Gestation and Lactation

While legacy higher-chlorinated PCBs are widely accepted to be developmental neurotoxicants that cause cognitive deficits, virtually nothing is known about the developmental neurotoxicity (DNT) potential of lower-chlorinated (LC) PCBs. Additionally, the influence of metabolism on DNT outcomes is largely unknown despite evidence that toxicity can vary between parent congeners and their metabolites. To address these critical gaps, we examined behavioral outcomes in juvenile mice exposed to PCB 11, a prevalent LC-PCB, at 0, 0.1, 1 or 6mg/kg/d in the maternal diet throughout gestation and lactation. Behavior was compared between mice with distinct cytochrome P450 (CYP) profiles: wildtype (WT) C57BL/6J, Cyp2abfgs gene cluster knockout (CYP-Null), and CYP-Null that express human CYP2A6 (2A6-Hum). PCB 11 increased body weight in WT pups and CYP-Null and 2A6-Hum dams but did not alter other indices of maternal and pup toxicity. PCB 11 reduced ultrasonic vocalizations in WT and 2A6-Hum but not CYP-Null pups. CYP-Null mice exposed to 0.1 and 6.0mg/kg/d PCB 11 showed increased exploratory behavior, whereas WT and 2A6-Hum mice were unaffected. Genotype-, PCB 11 dose-, and sex-dependent impairments in sociability, social novelty, and novel object recognition memory but not spontaneous alternation were observed. PCB 11 metabolites but not the parent congener were detected in serum from P21 pups in the 6.0mg/kg/d dose group only; neither PCB 11 nor its metabolites were detected in P35 serum. These findings suggest that developmental PCB 11 exposure alters social and cognitive behavior, and that CYP-mediated metabolism modifies susceptibility to PCB-induced DNT.