Estrogen-Like Effects Of Cadmium In Male Mice And The Involvement Of Mapks Pathway

Cadmium is a ubiquitous toxicant of environmental concern, classified as a category 1 human carcinogen. Clear estrogen-like effects of cadmium have been reported in ovariectomized rats after a single dose. Recent epidemiological findings might suggest increased risk of hormone-related cancers such as cancer of the endometrium and breast. However, the specific molecular mechanism of action is unknown. Recently, we have shown that estrogen-like effects of cadmium in female mice do not appear to be mediated via the classical estrogen receptor transcriptional pathway. However, some estrogen like effects, possibly mediated via the non-classical estrogen signaling pathway were observed. The aim of the present study was to investigate the estrogen-like effects of cadmium in male mice. ERE-luc male mice were injected subcutaneously with CdCl 2 at 0.5, 5, 50 or 500 µg/kg b.w. or with 17α-ethinylestradiol (EE2) on three consecutive days. Testicular weights and histology, body and organ weight, Cd-tissue retention, activation of MAPK pathways and ERE dependent luciferase expression were investigated. Body weight and relative liver and kidney weights were not altered in any of the CdCl 2 or EE2 treated animals as compared to the control. Relative testis weights were significantly decreased in 0.5 and 50µg CdCl 2 /kg b.w. treated animals as compared to control. Testicular histology analysis showed no significant changes in the tubulus diameter and epithelial thickness at stage VII, however some apoptotic cells were observed in mice treated with CdCl 2 . No significant alterations in ERE mediated luciferase activity were detected in any of the CdCl 2 treated groups. Phosphorylation of Mdm2 was significantly increased at relatively low-dose of CdCl 2 (5µg/kg b.w.), whereas no significant changes in phosphorylation of Akt were observed in CdCl 2 or EE2 treated animals. Phosphorylation of Erk was found to be significantly increased after exposure to 0.5, 5 and 50µg of CdCl 2 /kg b.w. as compared to control. Gene expression of c-myc, c-fos, c-jun and p53 appeared to be decreased at relatively low dose of CdCl 2 (5µg/kg b.w). No significant changes were observed in the expression of HSP32, p38, SP1 or ER-alpha after CdCl 2 exposure. In conclusion the results suggest the involvement of MAPKs signaling pathways in cadmium induced effects in vivo after short term exposure at the doses investigated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1321. doi:10.1158/1538-7445.AM2011-1321