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
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...
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2021.766826/full |
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| author | Sunjay Sethi Kimberly P. Keil Stietz Anthony E. Valenzuela Carolyn R. Klocke Jill L. Silverman Jill L. Silverman Birgit Puschner Isaac N. Pessah Isaac N. Pessah Pamela J. Lein Pamela J. Lein |
| author_facet | Sunjay Sethi Kimberly P. Keil Stietz Anthony E. Valenzuela Carolyn R. Klocke Jill L. Silverman Jill L. Silverman Birgit Puschner Isaac N. Pessah Isaac N. Pessah Pamela J. Lein Pamela J. Lein |
| author_sort | Sunjay Sethi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T03:04:47Z |
| format | Article |
| id | doaj.art-b3ed7b2652ab4f929573d3ca75980c29 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-23T03:04:47Z |
| publishDate | 2021-12-01 |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-b3ed7b2652ab4f929573d3ca75980c292022-12-21T18:02:20ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-12-011510.3389/fnins.2021.766826766826Developmental 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 CalciumSunjay Sethi0Kimberly P. Keil Stietz1Anthony E. Valenzuela2Carolyn R. Klocke3Jill L. Silverman4Jill L. Silverman5Birgit Puschner6Isaac N. Pessah7Isaac N. Pessah8Pamela J. Lein9Pamela J. Lein10Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, Davis, CA, United StatesThe MIND Institute, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesThe MIND Institute, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesThe MIND Institute, University of California, Davis, Davis, CA, United StatesPolychlorinated 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.https://www.frontiersin.org/articles/10.3389/fnins.2021.766826/fullFMR1 permutationgene-environment interactionneurodevelopmental disordersryanodine receptorsex differencessocial behavior |
| spellingShingle | Sunjay Sethi Kimberly P. Keil Stietz Anthony E. Valenzuela Carolyn R. Klocke Jill L. Silverman Jill L. Silverman Birgit Puschner Isaac N. Pessah Isaac N. Pessah Pamela J. Lein Pamela J. Lein 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 Frontiers in Neuroscience FMR1 permutation gene-environment interaction neurodevelopmental disorders ryanodine receptor sex differences social behavior |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | FMR1 permutation gene-environment interaction neurodevelopmental disorders ryanodine receptor sex differences social behavior |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2021.766826/full |
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