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

Abstract

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−/−::Ahrb1 C57BL6/J mice compared with wild‐type mice (Ahrb1 = high AHR affinity). Here we exposed gravid Cyp1a2−/−::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2). PCB‐exposed F1 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. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild‐type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de‐/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.

Contributions of cholinergic receptor muscarinic 1 and CYP1A2 gene variants on the effects of plasma ratio of clozapine/N-desmethylclozapine on working memory in schizophrenia

“…Our results corroborate these reports demonstrating an effect of CYP1A2 genotype and smoking status on CLZ levels, with *1F/*1F smokers showing lower CLZ levels than non-smokers of the same genotype. It is important to note there are environmental pollutants other than tobacco smoke, including polychlorinated biphenyls, which have affinity for AhRs and can contribute to regulating CYP1A2 gene activity and as a result, may also affect CLZ metabolism (Hufgard et al, 2019).…”

Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review)

“…Poor-affinity AhRs and high protein levels of CYP1A2 in maternal liver cells provided important protection to the offspring against the sensitivity to gestational PcBs exposure (60)(61)(62). conversely, high-affinity AhRs were found to respond to low levels of dL-PcBs, while the cYP1A2-mediated detoxification pathway could sequester DL-PCBs to prevent transfer to the offspring (60).…”