Abstract:
Polychlorinated biphenyls (PCBs) are persistent environmental contaminants that continue to pose health risks despite being banned decades ago. Developmental exposure to PCBs has been associated with neurodevelopmental disorders that exhibit pronounced sex-specific patterns. However, previous research has focused on individual organ systems, limiting understanding of how PCBs affect integrated physiological networks during development.We investigated whether maternal PCB exposure causes sex-specific alterations across the gut-liver-brain axis using the Fox River Mixture, an environmentally relevant PCB mixture reflecting contemporary human exposure patterns. Pregnant C57BL/6J mouse dams were exposed to vehicle or PCB mixture (0.1, 1.0, or 6.0 mg/kg/day) throughout gestation and lactation, with offspring assessed at multiple developmental timepoints for behavioral, microbiome, metabolomic, and hepatic transcriptomic outcomes. Maternal PCB exposure induced dose-dependent gut microbiome disruption, enhanced hepatic xenobiotic processing, and sex-specific alterations in hepatic type 1 deiodinase (DIO1) expression. Males showed dose-dependent DIO1 upregulation while females exhibited non-monotonic responses. By PND28, distinct sex-specific patterns at the transcriptomic(?) level emerged: males exhibited extensive gut-liver molecular connectivity (>7,000 significant correlations) with enhanced hepatic detoxification responses and dose-dependent DIO1 upregulation, while females showed focused connectivity patterns in molecular networks connectivity (<3,000 correlations) with inflammatory liver activation and non-monotonic DIO1 responses. At PND35, a reversal of vulnerability was observed: males showed behavioral resilience despite continued molecular alterations, while females developed significant social memory deficits at low and medium doses with concurrent thyroid hormone suppression. Integration of microbiome, metabolomic, and transcriptomic data revealed fundamentally different network architectures between sexes. Males developed redundant, highly interconnected networks with balanced hub distribution across bacterial species, metabolites, and hepatic genes, providing system robustness. Females showed hierarchical networks dominated by specific bacterial super-hubs, creating efficiency but increased vulnerability to disruption. These architectural differences correlated with behavioral outcomes, with network topology metrics predicting functional resilience versus vulnerability. This work provides comprehensive evidence that maternal PCB exposure causes persistent, sex-specific alterations across the gut-liver-brain axis through fundamentally different biological strategies. The identification of sex-specific DIO1 regulation as a mechanism underlying differential thyroid hormone disruption, combined with distinct microbiome-metabolite-transcriptome network architectures, reveals how the same environmental exposure leads to divergent developmental outcomes. These findings emphasize the critical importance of considering sex as a biological variable in environmental health risk assessment and suggest that current regulatory frameworks based on single-sex studies may inadequately protect vulnerable populations.