Unaltered Hepatic Wound healing Response in Male Rats with Ancestral Liver Injury

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Oct 10

PMID 37816736

Authors

Johanna Beil

Juliane Perner

Lena Pfaller

Marie-Apolline Gerard

Alessandro Piaia

Arno Doelemeyer

Adi Wasserkrug Naor

Lori Martin

Aline Piequet

Valerie Dubost

Salah-Dine Chibout

Jonathan Moggs

Remi Terranova

Affiliations

Soon will be listed here.

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 (CCl) in male rats. Here, we comprehensively investigate the transgenerational effects by repeating the original CCl 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.

References

Anway M, Cupp A, Uzumcu M, Skinner M . Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308(5727):1466-9. PMC: 11423801. DOI: 10.1126/science.1108190. View

Dias B, Ressler K . Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2013; 17(1):89-96. PMC: 3923835. DOI: 10.1038/nn.3594. View

Gapp K, van Steenwyk G, Germain P, Matsushima W, Rudolph K, Manuella F . Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol Psychiatry. 2018; 25(9):2162-2174. PMC: 7473836. DOI: 10.1038/s41380-018-0271-6. View

Fullston T, Ohlsson Teague E, Palmer N, DeBlasio M, Mitchell M, Corbett M . Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J. 2013; 27(10):4226-43. DOI: 10.1096/fj.12-224048. View

Radford E, Ito M, Shi H, Corish J, Yamazawa K, Isganaitis E . In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science. 2014; 345(6198):1255903. PMC: 4404520. DOI: 10.1126/science.1255903. View

Veenendaal M, Painter R, de Rooij S, Bossuyt P, van der Post J, Gluckman P . Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. BJOG. 2013; 120(5):548-53. DOI: 10.1111/1471-0528.12136. View

Nilsson E, Sadler-Riggleman I, Skinner M . Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet. 2018; 4(2):dvy016. PMC: 6051467. DOI: 10.1093/eep/dvy016. View

Carone B, Fauquier L, Habib N, Shea J, Hart C, Li R . Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010; 143(7):1084-96. PMC: 3039484. DOI: 10.1016/j.cell.2010.12.008. View

Iqbal K, Tran D, Li A, Warden C, Bai A, Singh P . Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogramming. Genome Biol. 2015; 16:59. PMC: 4376074. DOI: 10.1186/s13059-015-0619-z. View

10.

Cartier J, Smith T, Thomson J, Rose C, Khulan B, Heger A . Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations. Genome Biol. 2018; 19(1):50. PMC: 5891941. DOI: 10.1186/s13059-018-1422-4. View

11.

Francis G . Too much success for recent groundbreaking epigenetic experiments. Genetics. 2014; 198(2):449-51. PMC: 4196602. DOI: 10.1534/genetics.114.163998. View

12.

Schneider S, Kaufmann W, Buesen R, van Ravenzwaay B . Vinclozolin--the lack of a transgenerational effect after oral maternal exposure during organogenesis. Reprod Toxicol. 2008; 25(3):352-60. DOI: 10.1016/j.reprotox.2008.04.001. View

13.

Heard E, Martienssen R . Transgenerational epigenetic inheritance: myths and mechanisms. Cell. 2014; 157(1):95-109. PMC: 4020004. DOI: 10.1016/j.cell.2014.02.045. View

14.

Reik W, Dean W, Walter J . Epigenetic reprogramming in mammalian development. Science. 2001; 293(5532):1089-93. DOI: 10.1126/science.1063443. View

15.

Li Y, Sasaki H . Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming. Cell Res. 2011; 21(3):466-73. PMC: 3193417. DOI: 10.1038/cr.2011.15. View

16.

Cavalli G, Heard E . Advances in epigenetics link genetics to the environment and disease. Nature. 2019; 571(7766):489-499. DOI: 10.1038/s41586-019-1411-0. View

17.

Horsthemke B . A critical view on transgenerational epigenetic inheritance in humans. Nat Commun. 2018; 9(1):2973. PMC: 6065375. DOI: 10.1038/s41467-018-05445-5. View

18.

Zeybel M, Hardy T, Wong Y, Mathers J, Fox C, Gackowska A . Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med. 2012; 18(9):1369-77. PMC: 3489975. DOI: 10.1038/nm.2893. View

19.

Tsuchida T, Lee Y, Fujiwara N, Ybanez M, Allen B, Martins S . A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018; 69(2):385-395. PMC: 6054570. DOI: 10.1016/j.jhep.2018.03.011. View

20.

Dong S, Chen Q, Song Y, Sun Y, Wei B, Li X . Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. J Toxicol Sci. 2016; 41(4):561-72. DOI: 10.2131/jts.41.561. View