Low-dose tire wear chemical 6PPD-Q exposure elicit fatty liver via promoting fatty acid biosynthesis in ICR mice.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) as a major metabolite of tire wear chemical 6PPD has been demonstrated to be an emerging burden of exposure in human populations, via contamination from drinking water, air particulate matter and food sources. Whilst increasing attention has been moved toward its adverse effect, the potential hepatotoxicity of 6PPD-Q in mammals at realistic dose remains unknown. Here, the toxic effects of 6PPD-Q at environmentally relevant dose on the liver of adult mice and its underlying mechanism were investigated through an integrative approach combining transcriptomic and lipidomic analyses. We found that 6PPD-Q exposure induced excessive lipid deposition following three weeks of exposure, ultimately contributing to the pathogenesis of fatty liver disease. Mechanistically, 6PPD-Q exposure caused a remarkable increase in the contents of fatty acids within the hepatic tissue of mice by enhancing their biosynthesis, thereby facilitating lipid deposition. In summary, this study provides a new understanding on the endocrine disrupting effects of 6PPD-Q on hepatic lipid metabolism and how it may contribute to elevated risk of fatty liver disease. Our findings call for a potential public health attention on the risk assessment of 6PPD-Q, particularly towards the risk of chronic metabolic diseases.