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. 2025 Sep:118:104773.
doi: 10.1016/j.etap.2025.104773. Epub 2025 Jul 22.

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

Kilian Petitjean  1 , Giovanna Dicara  1 , Sébastien Bristeau  2 , Hugo Coppens-Exandier  1 , Laurence Amalric  2 , Nicole Baran  2 , Camille C Savary  3 , Anne Corlu  1 , Pascal Loyer  1 , Bernard Fromenty  4
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Free article

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

Kilian Petitjean et al. Environ Toxicol Pharmacol. 2025 Sep.
Free article

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. MnCl2 treatment reproduced these effects. Maneb or MnCl2 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 MnCl2. Maneb, or MnCl2, 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.

Keywords: Dithiocarbamates; Liver; Maneb; Manganese; Pesticides; Steatosis.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bernard Fromenty reports financial support was provided by Office Français de la Biodiversité. Kilian Petitjean reports financial support was provided by Cancéropôle du Grand Ouest. Hugo Coppens-Exandier reports financial support was provided by Association Nationale de la Recherche et de la Technologie. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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