RISING STARS: Sex differences in toxicant-associated fatty liver disease

Based on biological sex, the consequential health outcomes from exposures to environmental chemicals or toxicants can differ in disease pathophysiology, progression, and severity. Due to basal differences in cellular and molecular processes resulting from sexual dimorphism of organs including the liver and additional factors influencing 'gene-environment' interactions, males and females can exhibit different responses to toxicant exposures. Associations between environmental/occupational chemical exposures and fatty liver disease (FLD) have been well-acknowledged in human epidemiologic studies and their causal relationships demonstrated in experimental models. However, studies related to sex differences in liver toxicology are still limited to draw any inferences on sex-dependent chemical toxicity. The purpose of this review is to highlight the present state of knowledge on the existence of sex differences in toxicant-associated FLD (TAFLD), discuss potential underlying mechanisms driving these differences, implications of said differences on disease susceptibility, and emerging concepts. Chemicals of interest include various categories of pollutants that have been investigated in TAFLD, namely persistent organic pollutants, volatile organic compounds, and metals. Insight into research areas requiring further development is also discussed, with the objective of narrowing the knowledge gap on sex differences in environmental liver diseases. Major conclusions from this review exercise are that biological sex influences TAFLD risks, in part due to (i) toxicant disruption of growth hormone and estrogen receptor signaling, (ii) basal sex differences in energy mobilization and storage, and (iii) differences in chemical metabolism and subsequent body burden. Finally, further sex-dependent toxicological assessments are warranted for the development of sex-specific intervention strategies.