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.
Highlights
The prevalence of neurodevelopmental disorders, and in particular, autism spectrum disorder, is increasing worldwide (Landrigan et al, 2012; Baio et al, 2018), and several studies have documented that this is not due solely to increased awareness and expanded diagnostic criteria (Bishop et al, 2008; Coo et al, 2008; Hertz-Picciotto and Delwiche, 2009)
While dam weight at weaning was not altered by Polychlorinated biphenyls (PCBs) exposure, there was a significant main effect of genotype, with double mutant (DM) dams weighing significantly more than WT dams, T4826I dams weighing significantly more than CGG dams, and CGG dams weighing significantly less than DM dams (Matelski et al, 2020)
We tested the effect on the number of ultrasonic calls at P7 of developmental exposure to the MARBLES PCB mix, expression of genetic mutations that alter the fidelity of calcium signaling, singly and combined environmental and genetic factors
Summary
The prevalence of neurodevelopmental disorders, and in particular, autism spectrum disorder, is increasing worldwide (Landrigan et al, 2012; Baio et al, 2018), and several studies have documented that this is not due solely to increased awareness and expanded diagnostic criteria (Bishop et al, 2008; Coo et al, 2008; Hertz-Picciotto and Delwiche, 2009). The rapid rise in the prevalence of autism spectrum disorder coupled with evidence that single genetic factors alone account for only a percentage of cases (El-Fishawy and State, 2010; Herbert, 2010; Hallmayer et al, 2011; Weintraub, 2011; Landrigan et al, 2012) strongly support a role for environmental factors in determining individual risk and/or severity of these and other neurodevelopmental disorders (Sealey et al, 2016; Lyall et al, 2017). PCB production was banned worldwide in the early 2000s, human exposures to these pollutants continue, in part because of the environmental persistence of the legacy PCBs found in the commercial PCB mixture, and because of their release from PCB-containing hazardous waste sites, aging equipment, and building materials (Hornbuckle and Robertson, 2010; Klosterhaus et al, 2014; Grimm et al, 2015). The predominant routes of human exposure to both legacy and contemporary PCBs are ingestion and inhalation (Ampleman et al, 2015), and women of childbearing age continue to have quantifiable PCB levels in their serum (Koh et al, 2015; Granillo et al, 2019)
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