Long-term low-dose N, N-dimethylformamide exposure disturbs hepatic lipid and glucose homeostasis in mice

N, N-dimethylformamide (DMF) is a widely used industrial solvent with well-documented hepatotoxicity at high exposure levels. However, some epidemiological studies suggest that occupational exposure below the current occupational exposure limits (OELs) may still have adverse effects on workers. This study was designed to investigate the hepatotoxicity of subacute (28 days) and chronic (6 months) DMF exposure at OEL-relevant levels in mice. Mice exposed to 75 mg/kg bw DMF (a dose equivalent to the OEL of 20 mg/m³) for 28 days showed no signs of liver injury, while higher doses (150 and 300 mg/kg bw) led to increased serum aminotransferase activities, elevated liver weight/body weight ratio, and reduced hepatic lipid levels. However, 6 months of DMF exposure at 75 mg/kg bw caused a significant reduction in liver lipid content, activation of AMPK, and suppression of SREBP-1c, which were accompanied by elevated fasting blood glucose (FBG) levels, increased area under the curve (AUC) in glucose tolerance tests (GTTs), and enhanced lipolysis in white adipose tissue. Increased liver weight/body weight ratio, upregulation of AMPK and p-AMPK protein expression, white adipose tissue lipolysis, elevated FBG level, and increased AUC in GTTs were also observed in mice exposed to 37.5 mg/kg bw DMF. These results indicate that chronic DMF exposure at current OELs may disrupt hepatic metabolic homeostasis, highlighting the necessity to reestablish the OELs for DMF. Further validation of these results using an inhalation exposure model in both male and female mice, with dosimetry accurately bridging to human occupational exposure, is warranted.