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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.

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Title: 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.
Authors: Petitjean, Kilian1 (AUTHOR), Dicara, Giovanna1 (AUTHOR), Bristeau, Sébastien2 (AUTHOR), Coppens-Exandier, Hugo1 (AUTHOR), Amalric, Laurence2 (AUTHOR), Baran, Nicole2 (AUTHOR), Savary, Camille C.3 (AUTHOR), Corlu, Anne1 (AUTHOR), Loyer, Pascal1 (AUTHOR), Fromenty, Bernard1 (AUTHOR) bernard.fromenty@inserm.fr
Source: Environmental Toxicology & Pharmacology. Sep2025, Vol. 118, pN.PAG-N.PAG. 1p.
Subject Terms: *Pesticides, Mancozeb, Fatty liver, Hepatotoxicology, Low density lipoproteins, Metabolic disorders, Cytochrome P-450
Abstract: 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. [ABSTRACT FROM AUTHOR]
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Abstract: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. [ABSTRACT FROM AUTHOR]
ISSN:13826689
DOI:10.1016/j.etap.2025.104773