Department of Medicine, School of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville, Louisville, Kentucky, USA.
UofL Superfund Research Center, University of Louisville, Louisville, Kentucky, USA.
J Endocrinol. 2023 Jun 16;258(1). doi: 10.1530/JOE-22-0247. Print 2023 Jul 1.
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.
基于生物性别，暴露于环境化学物质或有毒物质对健康的影响可能在疾病病理生理学、进展和严重程度上有所不同。由于器官（包括肝脏）的细胞和分子过程存在基础差异，以及影响“基因-环境”相互作用的其他因素，男性和女性对有毒物质暴露的反应可能不同。在人类流行病学研究中已经充分认识到环境/职业化学暴露与脂肪肝疾病（FLD）之间的关联，并在实验模型中证明了它们的因果关系。然而，关于肝脏毒理学中性别差异的研究仍然有限，无法对化学毒性的性别依赖性得出任何推论。本综述的目的是强调目前关于有毒物质相关 FLD（TAFLD）中性别差异的知识现状，讨论导致这些差异的潜在机制，这些差异对疾病易感性的影响以及新兴概念。感兴趣的化学物质包括在 TAFLD 中研究过的各种类别污染物，即持久性有机污染物、挥发性有机化合物和金属。还讨论了需要进一步发展的研究领域的见解，目的是缩小环境性肝脏疾病中性别差异的知识差距。本综述的主要结论是，生物性别影响 TAFLD 风险，部分原因是（i）有毒物质破坏生长激素和雌激素受体信号，（ii）能量动员和储存的基础性别差异，以及（iii）化学代谢和随后的体内负荷的差异。最后，需要进一步进行依赖于性别的毒理学评估，以制定针对特定性别的干预策略。
