Developmental Exposure to a Human-Relevant Polychlorinated Biphenyl Mixture Causes Behavioral Phenotypes That Vary by Sex and Genotype in Juvenile Mice Expressing Human Mutations That Modulate Neuronal Calcium

Abstract

Polychlorinated biphenyls (PCBs) are putative environmental risks for neurodevelopmental disorders. Here, we tested two hypotheses: (1) developmental exposure to a human-relevant PCB mixture causes behavioral phenotypes relevant to neurodevelopmental disorders; and (2) expression of human mutations that dysregulate neuronal Ca2+ homeostasis influence sensitivity to behavioral effects of developmental PCB exposures. To test these hypotheses, we used mice that expressed a gain-of-function mutation (T4826I) in ryanodine receptor 1 (RYR1), the X-linked fragile X mental retardation 1 (FMR1) CGG repeat expansion or both mutations (double mutant; DM). Transgenic mice and wildtype (WT) mice were exposed to the MARBLES PCB mix at 0, 0.1, 1, and 6 mg/kg/day in the maternal diet throughout gestation and lactation. The MARBLES PCB mix simulates the relative proportions of the 12 most abundant PCB congeners found in the serum of pregnant women at increased risk for having a child with a neurodevelopmental disorder. We assessed ultrasonic vocalizations at postnatal day 7 (P7), spontaneous repetitive behaviors at P25-P30, and sociability at P27-P32. Developmental PCB exposure reduced ultrasonic vocalizations in WT litters in all dose groups, but had no effect on ultrasonic vocalizations in transgenic litters. Developmental PCB exposure significantly increased self-grooming and decreased sociability in WT males in the 0.1 mg/kg dose group, but had no effect on WT females in any dose group. Genotype alone influenced ultrasonic vocalizations, self-grooming and to a lesser extent sociability. Genotype alone also influenced effects of PCBs on sociability. PCB levels in the brain tissue of pups increased in a dose-dependent manner, but within any dose group did not differ between genotypes. In summary, developmental PCB exposure phenocopied social behavior phenotypes observed in mice expressing human mutations that modify intracellular Ca2+ dynamics, and expression of these mutations alleviated PCB effects on ultrasonic vocalizations and repetitive behavior, and modified the dose-response relationships and sex-dependent effects of PCB effects on social behavior. These findings suggest that: (1) developmental PCB exposure causes behavioral phenotypes that vary by sex and genotype; and (2) sex-specific responses to environmental factors may contribute to sex biases in the prevalence and/or severity of neurodevelopmental disorders.

Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

“…Furthermore, in the MARBLES cohort, PCBs were detected in the serum of the pregnant mothers at levels that were experimentally shown to impact neurodevelopmental processes in model systems ( Sethi et al, 2017a , 2019 ). When C57BL/6J mice were prenatally exposed to the MARBLES PCB mixture at 0.1 or 1.0 mg/kg/day through maternal diet, postnatal brain (~1 month old) showed PCB levels comparable to those reported in human samples ( Lanting et al, 1998 ; Mitchell et al, 2012 ), coincident with changes in the dendritic morphology of hippocampal and cortical pyramidal neurons and changes in ASD-relevant behaviors ( Keil Stietz et al, 2021 ; Sethi et al, 2021 ).…”

Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders

“…In that study, dams were orally administered a PCB mixture from 2-weeks prior to mating until pup weaning (P21). Ultrasonic vocalizations at P7 were diminished in all three mutant pup genotypes while both male and female T4826I and DM pups exhibited high spontaneous grooming behavior ( Sethi et al, 2021 ). Further, studies from the same group found that PCBs promote synaptogenesis in cultured hippocampal neurons, as evidenced by increased dendritic spines and miniature excitatory postsynaptic currents ( Lesiak et al, 2014 ).…”

“… Sethi et al (2021) conducted a follow-up study to understand the interaction of Ryr1 and Fmr1 and polychlorinated-biphenyls (PCBs) exposure in ASD-like behaviors ( Sethi et al, 2021 ). PCBs comprise environmental contaminants with established neurodevelopmental consequences that exert their neurotoxic effects by binding to the RyRs ( Pessah et al, 2010 ).…”

Machine Learning-Assisted Identification and Quantification of Hydroxylated Metabolites of Polychlorinated Biphenyls in Animal Samples

“…We also investigated metabolites of PCB 28 in the liver from a mouse exposed during gestation and lactation to a PCB mixture. − Based on the MS transition m / z 286 → 243, we identified three trichlorinated MeO-PCB peaks (peaks 1, 2, and 3) corresponding to monohydroxylated metabolites of PCB 28 (Figure a). Based on the experimental and predicted RRT and MS/MS data, the weighted rank scores of all possible MeO-PCB 28 candidates (Figure S10) were calculated for the three MeO-PCB 28 peaks (Figure b).…”