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). Recent investigations reported oxidative stress-induced apoptosis in differentiated hepatocyte-like HepaRG cells after a single treatment with a 7-pesticide mixture that included chlorpyrifos, dimethoate, diazinon, iprodione, imazalil, and the dithiocarbamates maneb and mancozeb. These effects were reproduced by maneb, mancozeb, or manganese chloride (MnCl 2 ). Herein, differentiated HepaRG cells cultured for 2 weeks without (-FA) or with (+FA) a mixture of stearic and oleic acids were treated with this 7-pesticide mixture, maneb, mancozeb, or MnCl 2 along the same period. While these molecules did not induce neutral lipid accumulation in -FA-HepaRG cells, they worsened steatosis in +FA-HepaRG cells. Maneb or MnCl 2 impaired very low-density lipoprotein (VLDL) secretion and increased fatty acid uptake without altering mitochondrial fatty acid oxidation and de novo lipogenesis. Reduced VLDL secretion was associated with decreased mRNA levels of apolipoproteins B and C3 and microsomal triglyceride transfer protein. Zinc supplementation restored VLDL secretion, reduced fatty acid uptake and prevented the exacerbation of steatosis in +FA-HepaRG cells treated with mancozeb or MnCl 2 . The mixture, 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 while chlorpyrifos metabolism was unaffected. Hence, maneb, mancozeb and MnCl 2 disturb the metabolism of lipids and xenobiotics in HepaRG cells, in particular in fatty acid-exposed cells. These findings could have major pathophysiological consequences in dithiocarbamate-exposed individuals with MASLD.