期刊
ARCHIVES OF TOXICOLOGY
卷 91, 期 11, 页码 3677-3687出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-017-1999-5
关键词
Liver; Hedgehog pathway; Hepatic steroidogenesis; Androgenization; Estrus cycle; Infertility
类别
资金
- Federal Ministry of Education and Research (Germany) within the research network Systems Medicine of the Liver (LiSyM) [031L0054, 031L0037]
- Virtual Liver Network (VLN) [0315735, 0315736, 0315755, 0315775]
- Deutsche Forschungsgemeinschaft (Bonn, Germany) [MU 1727/2-1, SCHR 1323/21]
- Robert Bosch Foundation (Stuttgart, Germany)
The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据