The dithiocarbamate pesticides maneb and mancozeb disturb the metabolism of lipids and xenobiotics in an in vitro model of metabolic dysfunction-associated steatotic liver disease

Pesticides are increasingly recognized to be hepatotoxic, but less is known about their toxicity in metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, differentiated HepaRG cells cultured for 2 weeks without (-FA) or with (+FA) a mixture of fatty acids were treated with different pesticides, including maneb and mancozeb, during the same period. While maneb and mancozeb did not induce neutral lipid accumulation in -FA-HepaRG cells, they worsened steatosis in +FA-HepaRG cells. MnCl 2 treatment reproduced these effects. Maneb or MnCl 2 impaired very low-density lipoprotein (VLDL) secretion and increased fatty acid uptake. Zinc supplementation restored VLDL secretion, reduced fatty acid uptake, and prevented steatosis worsening in +FA-HepaRG cells treated with mancozeb or MnCl 2 . Maneb, or MnCl 2, also reduced the mRNA expression and activity of several cytochromes P450 in +FA- and -FA-HepaRG cells. This was associated with impaired biotransformation of diazinon. These findings could have major pathophysiological consequences in dithiocarbamate-exposed individuals with MASLD. • Pesticide hepatotoxicity is understudied in the setting of obesity-related steatosis • Maneb, mancozeb, or MnCl 2 worsens steatosis in HepaRG cells cultured with fatty acids • This effect is associated with reduced VLDL secretion and increased fatty acid uptake • Zinc supplementation prevents mancozeb or MnCl 2 -induced steatosis • Maneb or MnCl 2 also impairs the activity of several cytochromes P450 in HepaRG cells