Hepatic Injury Caused by the Environmental Toxicant Vinyl Chloride is Sex-Dependent in Mice

Toxicol Sci. 2020 Mar 1;174(1):79-91. doi: 10.1093/toxsci/kfz236.

Abstract

Vinyl chloride (VC), a common industrial chemical, has been associated with hemangiosarcoma and toxicant-associated steatohepatitis (TASH) in men working at rubber-production plants. Our group previously demonstrated that chronic VC inhalation at environmentally relevant levels (< 1 ppm) in male mice exacerbated hepatic injury caused by high-fat diet (HFD) feeding. Because VC studies on TASH have only been performed in male models, the objective of this study is to examine VC inhalation in female mice in the context of TASH mechanisms. Male and female C57Bl/6 mice were fed either a low-fat diet or HFD and exposed to VC or room air using an inhalation chamber, for 12 weeks (6 h, 5 days/week); and plasma and liver samples were collected after euthanasia. Compared with males, females were less susceptible to HFD+VC-induced obesogenic effects demonstrated by lower body weight and fat composition. Histological analysis revealed that whereas VC exacerbated HFD-induced steatosis in males, this effect was absent in females. In addition, females were more resistant to VC-induced hepatic inflammation whereas males had increased liver weights and higher hepatic Tnfα mRNA levels. Systemic markers of hepatic injury, namely alanine aminotransaminase and thrombin/antithrombin levels were increased by HFD+VC co-exposures only in males. In addition, females did not show significant cell death as previously reported in males. Taken together, the results suggested that VC inhalation led to sex-dependent liver and metabolic toxicity. This study implicated the importance of assessing sex differences in environmental basic science and epidemiologic studies to better identify at-risk populations in both men and women.

Keywords: TASH; VC; inflammation; sex differences; steatosis; vinyl chloride.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Diet, High-Fat
  • Endoplasmic Reticulum Stress / drug effects
  • Environmental Pollutants / toxicity*
  • Fatty Liver / chemically induced*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Female
  • Gene Expression Regulation
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Risk Assessment
  • Sex Factors
  • Vinyl Chloride / toxicity*

Substances

  • Environmental Pollutants
  • Vinyl Chloride