Expression of the Human R163C-RYR1 Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice.

Overview

Authors: Christopher D. Barnhart¹, Rebecca J. Wilson¹, Sunjay Sethi¹, Hao Chen¹, Kim M. Truong¹, Izabela Kania-Korwel², Hans-Joachim Lehmler², Isaac N. Pessah¹, Pamela J. Lein¹

ORCID iDs: Rebecca J. Wilson, Hao Chen, Hans-Joachim Lehmler, Pamela J. Lein

Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA (R.J.W.)
Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA (H.-J.L.)

Institutions: University of California, Davis (United States); University of Iowa (United States)

Journal: International journal of molecular sciences, volume 27, issue 17, article 7801

Dates: received 28 July 2026; accepted 28 August 2026; published online 31 August 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.3390/ijms27177801 · PMID 42737696 · PMCID PMC13565785 · OpenAlex W7204934885

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: genetics / omics (modality), human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)

Methods: Statistics

Keywords: calcium-dependent signaling, neural exposome, neurodevelopmental disorders, neuronal connectivity, polychlorinated biphenyls, ryanodine receptor

MeSH: Neurotoxicity Syndromes*, Polychlorinated Biphenyls*, Ryanodine Receptor Calcium Release Channel*, Animals, Dendrites, Female, Humans, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mutation, Pyramidal Cells, Weaning (* major topic)

Topic: Toxic Organic Pollutants Impact (Health, Toxicology and Mutagenesis, Environmental Science), according to OpenAlex

Funding: National Institute of Environmental Health Sciences (R01 ES014901, R01 ES017425, P01 ES011269, T32 ES007059); U.S. Environmental Protection Agency (RD 83543201); Northern California Chapter of the ARCS fellowship program (P30 ES005605, P30 ES023513)

Citations: not cited yet (Europe PMC); 95 references in the paper

Abstract

Epidemiological studies have identified the developing brain as a target of concern for polychlorinated biphenyls (PCBs). In animal models, behavioral deficits caused by developmental exposure to PCBs have been associated with altered patterns of dendritic arborization in functionally relevant brain regions. In vitro studies revealed that PCB 95 promoted dendritic growth in primary rat hippocampal neuron–glia co-cultures via ryanodine receptor 1 (RYR1)-dependent Ca2+ signaling. However, it is not yet known whether RYR1 dysregulation contributes to disruption of dendritic morphogenesis in the intact developing brain or whether PCB 95 affects translationally relevant behavioral endpoints in juvenile animals. To address these data gaps, we assessed Morris water maze (MWM) performance and dendritic arborization of hippocampal CA1 pyramidal neurons in C57BL/6 mice heterozygous for the human R163C-RYR1 gain-of-function mutation (HET) and congenic wildtype (WT) littermates exposed to vehicle or PCB 95 at 0.1, 1.0, or 6.0 mg/kg/d in the dam’s diet from conception through weaning. MWM performance was not altered in HET vehicle controls relative to WT vehicle controls; however, compared to genotype-matched vehicle controls, spatial learning was impaired in WT and HET male and female weanlings in the 1.0 mg/kg/d PCB 95 dose group and WT males in the 6.0 mg/kg/d PCB 95 dose group. Spatial memory was altered only in WT females exposed to 1.0 or 6.0 mg/kg/d PCB 95. Sholl analyses of Golgi-stained hippocampal neurons in male and female WT and HET weanlings from the 1.0 mg/kg/d PCB 95 and vehicle groups indicated that relative to WT vehicle controls, basal dendritic arborization was significantly increased in HET vehicle controls and in PCB 95-exposed WT weanlings; however, PCB 95 did not alter basal dendritic growth in HET weanlings relative to genotype-matched vehicle controls. PCB 95 significantly reduced training-induced dendritic arborization in WT but not HET weanlings. Measurement of tritiated ryanodine ([3H]Ry) binding in cortical tissue from these same animals revealed interactions between genotype, PCB 95 exposure, and dose that altered [3H]Ry binding relative to WT vehicle controls. Quantitative analyses confirmed a dose-dependent increase in PCB tissue burden that was not significantly altered by genotype, MWM training, or sex. Serum levels of progesterone, estradiol, cortisol, and thyroid hormone (TH) and brain transcript levels of TH-responsive genes were not significantly altered by genotype or PCB 95 dose. These data demonstrate that PCB 95 caused behavioral deficits coincident with altered patterns of basal and training-induced dendritic arborization. Furthermore, behavioral and dendritic responses to PCB 95 were altered by expression of the human R163C-RYR1 gain-of-function mutation, supporting the involvement of RYR1-dependent mechanisms in PCB 95 DNT in vivo.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

doi:10.5061/dryad.vmcvdnd4t, at Dryad; found in “Data Availability Statement”

Data Availability Statement

The raw data supporting the conclusions of this article are available in the Dryad repository: DOI: 10.5061/dryad.vmcvdnd4t.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 6 keywords, 14 MeSH terms, 3 funders, 93 references.

Cite

This paper

Barnhart, C. D., Wilson, R. J., Sethi, S., Chen, H., Truong, K. M., Kania-Korwel, I., Lehmler, H.-J., Pessah, I. N., & Lein, P. J. (2026). Expression of the Human R163C-RYR1 Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice. International journal of molecular sciences, 27(17), 7801. https://doi.org/10.3390/ijms27177801

BibTeX

@article{barnhart2026expression, author = {Barnhart, Christopher D. and Wilson, Rebecca J. and Sethi, Sunjay and Chen, Hao and Truong, Kim M. and Kania-Korwel, Izabela and Lehmler, Hans-Joachim and Pessah, Isaac N. and Lein, Pamela J.}, title = {{Expression of the Human R163C-\<i\>RYR1\</i\> Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice}}, journal = {International journal of molecular sciences}, year = {2026}, month = aug, volume = {27}, number = {17}, pages = {7801}, publisher = {Multidisciplinary Digital Publishing Institute (MDPI)}, issn = {1422-0067}, doi = {10.3390/ijms27177801}, url = {https://doi.org/10.3390/ijms27177801}, pmid = {42737696}, pmcid = {PMC13565785} }

RIS

TY - JOUR AU - Barnhart, Christopher D. AU - Wilson, Rebecca J. AU - Sethi, Sunjay AU - Chen, Hao AU - Truong, Kim M. AU - Kania-Korwel, Izabela AU - Lehmler, Hans-Joachim AU - Pessah, Isaac N. AU - Lein, Pamela J. TI - Expression of the Human R163C-RYR1 Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice T2 - International journal of molecular sciences J2 - Int J Mol Sci PY - 2026 DA - 2026/08/31 VL - 27 IS - 17 SP - 7801 SN - 1422-0067 PB - Multidisciplinary Digital Publishing Institute (MDPI) DO - 10.3390/ijms27177801 UR - https://doi.org/10.3390/ijms27177801 LA - en ER -

CSL-JSON

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Expression of the Human R163C-<i>RYR1</i> Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice.

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Expression of the Human R163C-&lt;i&gt;RYR1&lt;/i&gt; Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice.

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Expression of the Human R163C-<i>RYR1</i> Gain-of-Function Mutation Modified 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Developmental Neurotoxicity in Weanling Mice.