Gestational Arsenic Exposure Induces Metabolic Dysfunction-Associated Fatty Liver Disease–like Phenotypes in Middle-Aged Offspring

Metabolic dysfunction-associated fatty liver disease (MAFLD) refers to hepatic steatosis accompanied by one of the following: type 2 diabetes, obesity, overweight, or metabolic dysfunction. Developmental arsenic (As) exposure is linked to metabolic disorders, but its effects on MAFLD-related phenotypes remain unclear. This study aims to assess the impact of prenatal As exposure on MAFLD-like phenotypes in adulthood offspring. Pregnant mice were given deionized water containing NaAsO2 at concentrations of 0, 1.5, and 15 mg/L throughout their pregnancy. Doses were selected based on environmentally relevant exposure (1.5 mg/L, L-As) and prior evidence of metabolic effects in rodents (15 mg/L, H–As). Gestational H–As exposure increased hepatic triglyceride content and enlarged hepatic lipid droplets in middle-aged offspring. Intraperitoneal glucose tolerance test and insulin tolerance test analyses revealed that prenatal L-As and H–As exposure impaired glucose and insulin tolerance in middle-aged offspring. White fat mass and adipocyte size were elevated in H–As exposed middle-aged offspring. Several metabolism-related hormones, including adiponectin, leptin, and insulin, were elevated, whereas glucagon-like peptide-1, a hormone secreted by the intestines, was reduced in H–As exposed female middle-aged offspring. These results demonstrate that prenatal As-alone promotes MAFLD-like phenotypes in middle-aged offspring, highlighting its role as an early life environmental trigger for metabolic disease.