Hedgehog signaling influences gender-specific response of liver to radiation in mice

It is unclear why the response to radiation in the female liver is different from that of the male liver. Hedgehog (Hh) that remains latent in healthy adult livers is activated in the injured liver and promotes the proliferation of progenitors and myofibroblastic hepatic stellate cells, leading to hepatic fibrosis.

These findings have led to the hypothesis that the gender-specific expression of Hh signaling could affect the different response of the female liver to radiation.

Male and female mice irradiated with a single dose of 6 Gy were killed at 1 week post irradiation, and the livers were collected for biochemical analysis.

A greater accumulation of fatty hepatocytes and apoptotic cells was observed in irradiated female mice. Sox-9 and pancytokeratin-positive cells were expanded in the livers of irradiated female, but not male, mice. The expression of the Hh ligand, Sonic Hh, Hh receptor, Smoothened, and Hh-target gene, Gli2, showed a greater increase in the liver of radiation-treated female. The levels of epithelial-to-mesenchymal transition (EMT)-stimulating factor, transforming growth factor-β, collagen α1, and N-cadherin were upregulated, while the EMT inhibitor, bmp7, was downregulated in the damaged liver of females compared to controls. In addition, increased fibrosis was seen in the injured livers of female mice. No significant changes in Hh expression and EMT were detected in the irradiated male mice.

These results demonstrated that the increased expression of Hh signaling contributed to the different repair process in the irradiated female mice by promoting proliferation of progenitor and EMT process.