Abstract
Azoxymethane (AOM) is a widely used carcinogen to study chemical-induced colorectal carcinogenesis and is an agent for studying fulminant hepatic failure. The inter-strain susceptibility to acute toxicity by AOM has been reported, but its association with host genetics or gut microbiota remains largely unexplored. Here a cohort of genetically diverse Collaborative Cross (CC) mice was used to assess the contribution of host genetics and the gut microbiome to AOM-induced acute toxicity. We observed variation in AOM-induced acute liver failure across CC strains. Quantitative trait loci (QTL) analysis revealed three chromosome regions significantly associated with AOM toxicity. Genes located within these QTL, including peroxisome proliferator-activated receptor alpha (Ppara), were enriched for enzyme activator and nucleoside-triphosphatase regulator activity. We further demonstrated that the protein level of PPARα in liver tissues from sensitive strains was remarkably lower compared to levels in resistant strains, consistent with protective role of PPAR family in liver injury. We discovered that the abundance levels of gut microbial families Anaeroplasmataceae, Ruminococcaceae, Lactobacillaceae, Akkermansiaceae and Clostridiaceae were significantly higher in the sensitive strains compared to the resistant strains. Using a random forest classifier method, we determined that the relative abundance levels of these microbial families predicted AOM toxicity with the area under the receiver-operating curve (AUC) of 0.75. Combining the three genetic loci and five microbial families increased the predictive accuracy of AOM toxicity (AUC of 0.99). Moreover, we found that Ruminococcaceae and Lactobacillaceae acted as mediators between host genetics and AOM toxicity. In conclusion, this study shows that host genetics and specific microbiome members play a critical role in AOM-induced acute toxicity, which provides a framework for analysis of the health effects from environmental toxicants.
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Acknowledgements
This work was supported by the Lawrence Berkeley National Laboratory Directed Research and Development (LDRD) program funding under contract DE AC02-05CH11231 (JHM and AMS). Additional support was provided by grants from the National Natural Science Foundation of China (No. 81872481) (YY).
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JHM and AMS designed the study. CZ, LH, SYL, SEC, AMS and JHM performed experiments and collected the data. CZ, HC, YZ and DWT performed data analysis. DWT, YY, FZ, SEC and YX contributed to data interpretation and critical revision of text. All the authors approved the manuscript for publication.
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Zhong, C., He, L., Lee, SY. et al. Host genetics and gut microbiota cooperatively contribute to azoxymethane-induced acute toxicity in Collaborative Cross mice. Arch Toxicol 95, 949–958 (2021). https://doi.org/10.1007/s00204-021-02972-x
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DOI: https://doi.org/10.1007/s00204-021-02972-x