Lucky grandchildren: Inbred mice whose grandparents developed liver fibrosis appear to be protected against the same disease

Background: Epigenetic mechanisms might modify the fibrogenic response to liver injury. Recently a history of CCl₄-induced liver damage was shown to result in an epigenetic suppressive adaptation of the wound healing response in male F2 rats (Zeybel et al. Nat Med 2012).

Our aim now was to investigate whether ancestral liver injury leads to mutligenerational reprogramming of the fibrotic response in inbred mouse strains.

Methods: To address this question we designed an experiment in which male mice from the BALB/cJ inbred strain were treated with CCl₄ intraperitoneally for six weeks to induce liver fibrosis. The mice were subsequently bred for two generations. Half of the resulting F2 generation was challenged with CCl₄ again for six weeks. The treated group was compared to control mice without induction of fibrosis in previous generations. Measurements were taken in 9 – 12 animals per treated group depending on analysis. Liver histopathology was assessed after staining of collagen, and hepatic collagen contents were quantified enzymatically. As markers to determine the severity of fibrosis we measured the hepatic expression levels of collagens I and III, transforming growth factor (TGF)-beta 1 and alpha-smooth muscle actin (SMA).

Results: Our findings provided clear indication for a significant decrease in fibrosis severity in animals with ancestors exposed to the hepatotoxin CCl₄. Collagen I expression decreased significantly as did collagen in histopathology. In line with these findings, alpha-SMA mRNA levels showed a trend to decrease in mice with a transgenerational background of fibrosis, and liver/body weight ratio showed similar alterations. Peculiarly, TGF-beta 1 mRNA levels increased, and collagen III expression did not differ significantly between pre-treated pedigrees and control progeny.

Discussion: This is the first data set to provide evidence for multigenerational epigenetic modulation of fibrogenesis in inbred mouse strains. We speculate that modifications of histones controlling the fibrogenic genes could result in the attenuation of fibrosis through an advantageous shift of the collagen I/III ratio. A myofibroblast-secreted soluble factor might stimulate heritable epigenetic signatures that allow the progeny to adapt to fibrogenic stimuli.

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