Sex-specific effects of early-life arsenic exposure on body weight, arsenic metabolism, and gut microbiome stability in C57BL/6J mice

Arsenic exposure in early-life is strongly linked to health risks for mothers and their offspring. Although the mechanisms by which arsenic induces the toxicity and health impacts remain unclear, the gut microbiome makes key contributions to the metabolism of arsenic. This study established a C57BL/6 mice model of pregnancy to explore the impact of exposure to environmental concentrations of arsenic on growth and gut microbiome dynamics in pregnant mice and their offspring. Maternal exposure to 0.10 mg/L arsenic during gestation (initiated at GD0 and GD14, respectively) and lactation elevated gut microbial diversity in pups at 3 weeks of age, with body weight markedly decreasing in the GD0 group but significantly increasing in the GD14 group. Compared to pups receiving solely a 5-week high-dose arsenic exposure (10.0 mg/L) during adolescence, those with early-life low-dose followed by the same adolescent high-dose exposure exhibited sex-specific alterations in gut microbiome and arsenic metabolism. At 8 weeks of age, this exposure promoted gut microbial diversity and network interactions in female pups, concurrently downregulating As V reduction genes and reducing kidney arsenic bioaccumulation. By contrast, male pups exhibited divergent responses, where arsenic exposure decreased microbial diversity and network interactions, accompanied by increased feces arsenic excretion and decreased liver arsenic bioaccumulation. This study highlights the short- and long-term impact of arsenic exposure on gut microbiome stability and the arsenic metabolic characteristics under different exposure conditions, which offers novel insights into the developmental toxicity of arsenic exposure in early life. Video Abstract