Unaltered hepatic wound healing response in male rats with ancestral liver injury

Johanna Beil, Juliane Perner, Lena Pfaller, Marie-Apolline Gérard, Alessandro Piaia, Arno Doelemeyer, Adi Wasserkrug Naor, Lori Martin, Aline Piequet, Valérie Dubost, Salah-Dine Chibout, Jonathan Moggs and Rémi Terranova ()
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Johanna Beil: Novartis, Biomedical Research
Juliane Perner: Novartis, Biomedical Research
Lena Pfaller: Novartis, Biomedical Research
Marie-Apolline Gérard: Novartis, Biomedical Research
Alessandro Piaia: Novartis, Biomedical Research
Arno Doelemeyer: Novartis, Biomedical Research
Adi Wasserkrug Naor: Novartis, Biomedical Research
Lori Martin: Novartis, Biomedical Research
Aline Piequet: Novartis, Biomedical Research
Valérie Dubost: Novartis, Biomedical Research
Salah-Dine Chibout: Novartis, Biomedical Research
Jonathan Moggs: Novartis, Biomedical Research
Rémi Terranova: Novartis, Biomedical Research

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The possibility that ancestral environmental exposure could result in adaptive inherited effects in mammals has been long debated. Numerous rodent models of transgenerational responses to various environmental factors have been published but due to technical, operational and resource burden, most still await independent confirmation. A previous study reported multigenerational epigenetic adaptation of the hepatic wound healing response upon exposure to the hepatotoxicant carbon tetrachloride (CCl4) in male rats. Here, we comprehensively investigate the transgenerational effects by repeating the original CCl4 multigenerational study with increased power, pedigree tracing, F2 dose-response and suitable randomization schemes. Detailed pathology evaluations do not support adaptive phenotypic suppression of the hepatic wound healing response or a greater fitness of F2 animals with ancestral liver injury exposure. However, transcriptomic analyses identified genes whose expression correlates with ancestral liver injury, although the biological relevance of this apparent transgenerational transmission at the molecular level remains to be determined. This work overall highlights the need for independent evaluation of transgenerational epigenetic inheritance paradigms in mammals.

Date: 2023
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DOI: 10.1038/s41467-023-41998-w

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