Assessing the Impact of Benzalkonium Chlorides on the Gut-Liver Axis

Abstract

Benzalkonium Chlorides (BACs) are highly effective disinfectants, widely used in consumer, clinical, food processing and agricultural settings. Recently, the Food and Drug Administration (FDA) called for additional safety data on BACs. Additionally, the recent COVID-19 pandemic has resulted in increased concentrations of BACs being detected in human blood samples as well as residential dust samples. Importantly, environmental toxicant exposure and the effects on the resident gut microbiome is becoming increasingly recognized as a unique mechanism of understanding human health and disease. The gut-liver axis is a unique, bidirectional link that has become recognized for the role it has in liver disease and impairment of liver function. We hypothesize is that exposure to BACs can impact the resident microbiome, which will lead to alterations in transcriptomic, sterol, lipid, and xenobiotic metabolism of the liver. In this dissertation, I describe a comprehensive animal study that elucidated BAC exposure effects on gut microbiome composition and diversity, unconjugated bile acid (BA) pools in biological extracts, and BAC and BAC metabolite profiles. Additionally, I report a thorough and comprehensive quantitation analysis of BAC and BAC metabolite distribution throughout brain, lung, blood, spleen, kidney, liver, duodenum, jejunum, ileum, large intestine, feces and urine in male and female BAC exposed mice. Next, I share a comprehensive multiomics analyses of BAC-induced changes to endogenous and exogenous metabolism in livers of BAC exposed mice including transcriptomics, sterolomics, lipidomics and cytochrome p450 activity. Finally, I conclude with overall conclusions and implications of this work, and provide insight into future studies that should be conducted. Together, this dissertation provides a comprehensive and rigorous comprehension of environmental toxicant exposure risk to human health by elucidating mechanisms by which BAC-exposure disrupts gut microbiome composition and diversity, and endogenous and exogenous metabolism in the liver.