Sex Differences in Paternal Arsenic-Induced Intergenerational Metabolic Effects Are Mediated by Estrogen

Authors

Yanfeng Xue
Yingyun Gong
Xin Li
Fei Peng
Guolian Ding
Zhao Zhang
Junchao Shi
Ilma Saleh Savul
Yong Xu
Qi Chen
Leng Han
Shengyong Mao
Zheng Sun

Publication Date

9-10-2023

Journal

Cell & Bioscience

DOI

10.1186/s13578-023-01121-4

PMID

37691128

PMCID

PMC10493026

PubMedCentral® Posted Date

9-10-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Arsenic exposure, Environmental health, Glucose and lipid metabolism, Estrogen signaling pathway, Epigenetic inheritance

Abstract

BACKGROUND: Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences.

METHODS: After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 mice, respectively. F0 females and all F1 mice drank normal water without iAs all the time.

RESULTS: We find that exposure of male mice to 250 ppb iAs leads to glucose intolerance and insulin resistance in F1 female offspring (iAsF1-F), with almost no change in blood lipid profiles. In contrast, F1 males (iAsF1-M) show lower liver and blood triglyceride levels than non-exposed control, with improved glucose tolerance and insulin sensitivity. The liver of F1 offspring shows sex-specific transcriptomic changes, with hepatocyte-autonomous alternations of metabolic fluxes in line with the sex-specific phenotypes. The iAsF1-F mice show altered levels of circulating estrogen and follicle-stimulating hormone. Ovariectomy or liver-specific knockout of estrogen receptor α/β made F1 females resemble F1 males in their metabolic responses to paternal iAs exposure.

CONCLUSIONS: These results demonstrate that disrupted reproductive hormone secretion in alliance with hepatic estrogen signaling accounts for the sex-specific intergenerational effects of paternal iAs exposure, which shed light on the sex disparities in long-term gene-environment interactions.

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