PCB-Exposed Gut Microbiota Recapitulate Neurobehavioral Deficits and Reprogram Hippocampal Transcriptomic Signatures
- 1Environmental and Molecular Toxicology, College of Agricultural Sciences, Oregon State University
Abstract
Polychlorinated biphenyls (PCBs) are persistent environmental pollutants associated with developmental neurotoxicity and autism spectrum disorder (ASD). However, whether PCB-induced alterations in gut microbiota contribute to neurodevelopmental toxicity independently of direct chemical exposure remains unclear. Here, we investigated whether transplantation of PCB-associated gut microbiota produces early neurobehavioral alterations and disrupts brain molecular pathways in offspring. Gut microbiota from conventional dams exposed to the Fox River PCB mixture (FRM; 6.0 mg/kg/day) or vehicle were transplanted into germ-free recipient females without direct PCB administration. At postnatal day 7 (P7), offspring underwent ultrasonic vocalization (USV) testing, whole-brain RNA sequencing (n = 4/sex/group), and untargeted serum metabolomics. Untargeted serum metabolomics were also performed in donor dams. PCB-associated fecal microbiota transplantation (FMT) significantly reduced offspring USVs, reproducing effects observed following direct maternal PCB exposure. Brain transcriptomics in offspring identified substantially more differentially expressed genes in males (9,339) than females (1,082), including 512 shared genes. Concordantly regulated genes revealed downregulation of neurotransmitter signaling and ion channel pathways alongside upregulation of RNA processing pathways. Male-associated responses involved altered protein synthesis and neuronal signaling, whereas female-associated responses involved DNA repair and extracellular matrix remodeling. Despite these molecular differences, behavioral responses showed no significant sex-dependent effect. Maternal metabolomics revealed increased bile acids and decreased indole-3-propionic acid, highlighting potential AhR-NF{kappa}B and bile acid-associated signaling mechanisms. Offspring metabolomics further identified alterations in lipid-associated metabolites and metabolic profiles. Collectively, these findings show that transferring PCB-exposed microbiota reproduces early neurobehavioral alterations and induces shared and sex-biased molecular responses, identifying the maternal gut microbiome as a candidate mediator linking PCB exposure to developmental neurotoxicity.
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BibTeX
@misc{suh2026pcbexposed,
title = {{PCB-Exposed Gut Microbiota Recapitulate Neurobehavioral Deficits and Reprogram Hippocampal Transcriptomic Signatures}},
author = {Y. P. Suh and R. J. Wilson and N. M. Breese and P. J. Lein and H.-J. Lehmler and J. Y. Cui},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764721},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764721v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - PCB-Exposed Gut Microbiota Recapitulate Neurobehavioral Deficits and Reprogram Hippocampal Transcriptomic Signatures
AU - Y. P. Suh
AU - R. J. Wilson
AU - N. M. Breese
AU - P. J. Lein
AU - H.-J. Lehmler
AU - J. Y. Cui
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764721
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764721v1
AB - Polychlorinated biphenyls (PCBs) are persistent environmental pollutants associated with developmental neurotoxicity and autism spectrum disorder (ASD). However, whether PCB-induced alterations in gut microbiota contribute to neurodevelopmental toxicity independently of direct chemical exposure remains unclear. Here, we investigated whether transplantation of PCB-associated gut microbiota produces early neurobehavioral alterations and disrupts brain molecular pathways in offspring. Gut microbiota from conventional dams exposed to the Fox River PCB mixture (FRM; 6.0 mg/kg/day) or vehicle were transplanted into germ-free recipient females without direct PCB administration. At postnatal day 7 (P7), offspring underwent ultrasonic vocalization (USV) testing, whole-brain RNA sequencing (n = 4/sex/group), and untargeted serum metabolomics. Untargeted serum metabolomics were also performed in donor dams. PCB-associated fecal microbiota transplantation (FMT) significantly reduced offspring USVs, reproducing effects observed following direct maternal PCB exposure. Brain transcriptomics in offspring identified substantially more differentially expressed genes in males (9,339) than females (1,082), including 512 shared genes. Concordantly regulated genes revealed downregulation of neurotransmitter signaling and ion channel pathways alongside upregulation of RNA processing pathways. Male-associated responses involved altered protein synthesis and neuronal signaling, whereas female-associated responses involved DNA repair and extracellular matrix remodeling. Despite these molecular differences, behavioral responses showed no significant sex-dependent effect. Maternal metabolomics revealed increased bile acids and decreased indole-3-propionic acid, highlighting potential AhR-NF{kappa}B and bile acid-associated signaling mechanisms. Offspring metabolomics further identified alterations in lipid-associated metabolites and metabolic profiles. Collectively, these findings show that transferring PCB-exposed microbiota reproduces early neurobehavioral alterations and induces shared and sex-biased molecular responses, identifying the maternal gut microbiome as a candidate mediator linking PCB exposure to developmental neurotoxicity.
ER -