Spatial transcriptomic profiling uncovers the molecular effects of the neurotoxicant polychlorinated biphenyls (PCBs) in the brains of adult mice

Abstract

Environmental toxicants, such as polychlorinated biphenyls (PCBs), are highly stable synthetic organic compounds that are present in air, water, and soil. PCBs have been identified in post-mortem human brains of individuals with neurodegenerative diseases, indicating a possible link between environmental factors and disease risk. Research has revealed an association between PCB exposure and cognitive decline. Therefore, it is crucial to evaluate how PCB mixtures relevant to humans affect brain function and cognition. To investigate the effects of PCBs on memory and transcriptomic profiles, we exposed adult male C57BL/6J mice orally to a synthetic PCB mixture daily. After seven weeks of exposure, the mice were assessed in a spatial object recognition task (SOR) to evaluate long-term spatial memory. Our findings showed that mice exposed to PCBs exhibited deficits in long-term spatial memory. To examine the molecular effects of PCB on the brain, we used a spatial transcriptomics technique to analyze gene expression changes in five brain regions: the hippocampus, neocortex, thalamus, caudal putamen, and fiber tracts. Our analysis of spatial gene expression revealed the molecular signatures influenced by PCB in these susceptible brain regions of mice. Network analysis suggests that these changes are associated with higher chlorinated PCBs present in the brain. Additionally, we show that PCB exposure disrupts the expression of tight junction proteins, which are crucial for maintaining the integrity of the blood-brain barrier (BBB). Thus, our results offer mechanistic insights into how PCB exposure affects brain function and cognition.