Inter‐ and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic

Advanced Science

Zhao Zhang¹  Leng Han¹  Yingyun Gong²  Paola Marcolongo³  Angiolo Benedetti³  Wenjun Zhou⁴  Guolian Ding⁴  Zheng Sun⁴  Xin Li⁴  Yanfeng Xue⁴  Shengyong Mao⁵ 

[1] Department of Biochemistry and Molecular Biology McGovern Medical School University of Texas Health Science Center at Houston Houston TX 77030 USA;Department of Endocrinology and Metabolism The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 China;Department of Molecular and Developmental Medicine University of Siena Siena 53100 Italy;Division of Endocrinology Department of Medicine Baylor College of Medicine Houston TX 77030 USA;National Center for International Research on Animal Gut Nutrition College of Animal Science and Technology Nanjing Agricultural University Nanjing 210095 China;

关键词: arsenic;    diabetes;    environmental health;    epigenetic inheritance;    metabolism;    obesity;   

DOI  :  10.1002/advs.202002715

来源: DOAJ

【 摘 要 】

Abstract The rise of metabolic disorders in modern times is mainly attributed to the environment. However, heritable effects of environmental chemicals on mammalian offsprings' metabolic health are unclear. Inorganic arsenic (iAs) is the top chemical on the Agency for Toxic Substances and Disease Registry priority list of hazardous substances. Here, we assess cross‐generational effects of iAs in an exclusive male‐lineage transmission paradigm. The exposure of male mice to 250 ppb iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males, without affecting body weight. Hepatic expression of glucose metabolic genes, glucose output, and insulin signaling are disrupted in F1 females. Inhibition of the glucose 6‐phosphatase complex masks the intergenerational effect of iAs, demonstrating a causative role of hepatic glucose production. F2 offspring from grandpaternal iAs exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and increased brown adipose thermogenesis. In contrast, F3 offspring of the male‐lineage iAs exposure show increased adiposity, especially on a high‐calorie diet. These findings have unveiled sex‐ and generation‐specific heritable effects of iAs on metabolic physiology, which has broad implications in understanding gene‐environment interactions.

【 授权许可】

Unknown