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.
Highlights
The rise of metabolism-related chronic diseases in industrialized society is mainly attributed to environmental factors because the population’s genetic makeup cannot be drastically altered in such a short period
The current evidence suggests hepatic glucose production as the underlying molecular mechanism: 1) female iAsF1 mice were intolerant to insulin as well as gluconeogenic substrates such as pyruvate or alanine as compared to conF1; 2) primary hepatocytes isolated from female iAsF1 mice showed enhanced glucose output than conF1; 3) female iAsF1 liver had a lower glycogen content than conF1 and reduced phosphorylation of FoxO1, a critical regulator of gluconeogenesis; 4) expression of gluconeogenic genes downstream of FoxO1 was altered in female iAsF1 liver; and 5) pharmacologic manipulation of the gluconeogenic enzyme system masked the glucose phenotype in iAsF1 females
DNA methylation is maintained by the opposing actions of two classes of enzymes, DNA methyltransferases (DNMTs) and demethylase family Ten–eleven translocations (TETs).[47,48] Inorganic arsenic (iAs) was shown to alter TET activities[49,50] and DNA methylation.[51,52,53,54,55,56,57,58]
Summary
The rise of metabolism-related chronic diseases in industrialized society is mainly attributed to environmental factors because the population’s genetic makeup cannot be drastically altered in such a short period. Industrialization in modern human history has been associated with widespread pollution of air, water, soil, and food.[1] Many developed countries have seen a steady reduction of pollution in the past few decades,[2,3] but it is unclear how cross-generational effects of environmental, chemical exposure in the descendants contribute to metabolic disorders later in life. The transgenerational effects of iAs have not been studied in mammals, the effect of early-life iAs exposure on later-life health has been characterized under the DOHaD paradigm.[18,19,20,21,22,23,24,25,26,27,28,29,30] We focused on an exclusive male-lineage exposure paradigm. We focused on the glucose tolerance phenotype in the F1 offspring, but adiposity and energy balance in the F2 and F3 generations
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