Sex-stratified Gut Microbiome Disruption is Associated with Altered Hepatic Gene Expression during Acute Azoxystrobin...

Azoxystrobin is a widely used fungicide that has been associated with to reproductive, neurological, and developmental defects. This chemical also disrupts gut microbial communities; however, if these perturbations contribute to the harms associated with exposure to azoxystrobin, this remains unclear. In this study, we investigated the effects of acute exposure to a series of concentrations (5-500 mg/kg) of azoxystrobin on the host and gut microbiota in zebrafish. Fecal amplicon and shotgun metagenomic sequencing was integrated with liver gene expression to quantify associations between microbiome disruption azoxystrobin toxicity in the host. Azoxystrobin exposure resulted in significant alteration in microbiome composition and functional potential in a dose- and sex-dependent manner. Microbial communities in exposed animals exhibited an increased abundance of xenobiotic metabolism pathways and decreased bacterial motility and lipopolysaccharide biosynthesis pathway metabolism. At the host level, histopathology identified increased biliary proliferation, most evident in medium- and high-dose fish. We also observed hepatic transcriptional changes consistent with a stress response, including altered redox-associated genes and reduced expression of lipid and small-molecule metabolic genes, with sex-stratified differences. Importantly, alterations in host transcriptional programming correlated with the compositional changes in exposed microbiota. Together, these results suggest concurrent impacts of azoxystrobin on gut microbiota and the liver implicate the microbiome as a potential contributor to changes in liver gene expression during exposure.