Transgenerational Effects of Paternal in Utero Arsenic Exposure on MASLD-like Phenotypes

Previous study indicated that early-life arsenic (As) exposure caused adulthood metabolic dysfunction-associated steatotic liver disease (MASLD)-like phenotypes. This study aimed to investigate the impacts of paternal in utero As exposure on MASLD-like phenotypes in offspring. Pregnant dams received NaAsO₂ (15 mg/L) through drinking water. In utero As-exposed male pups were designated as F0 mice and mated with untreated females to produce F1 offspring. F1 males were subsequently mated with untreated females to generate F2 offspring, both without further As exposure. MASLD-like phenotypes were evaluated in F1 and F2 offspring. On PNW28, As-exposed F1 offspring exhibited hepatic steatosis, glucose intolerance, insulin resistance, and obesity, accompanied by altered metabolic hormones, such as GLP-1, GIP, insulin, and ADPN. The core MASLD-like phenotypes, including hepatic steatosis, glucose intolerance and insulin resistance, exhibited transgenerational transmission from F1 to F2 generations. In F2 offspring, these metabolic abnormalities were detected at PNW45 but not at PNW28, predominantly in male offspring. In contrast, As-induced obesity and metabolic hormone alterations exhibited transgenerational attenuation. F2 offspring retained only adipocyte hypertrophy, with no significant changes in white or brown adipose tissue weight. Furthermore, hormonal alterations in F2 mice were limited to reduced GLP-1 and elevated ADPN levels, while other altered hormones normalized. This study is the first to confirm that paternal in utero As exposure causes MASLD-like phenotypes in F1 offspring and transgenerational transmission to F2 generation.