In vivo and in vitro evaluation and characterization of the estrogenic properties of uranium

Uranium (U) is the heaviest naturally occurring element and is most notably known for its radioactive properties. In the Four Corners region of the United States, which includes the Navajo Nation, extensive U mining occurred during the years of the Cold War. At the end of the Cold War, the U.S. government ceased to be the sole purchaser of U, and the U mining industry in the U.S. collapsed. In the aftermath of the collapsed U mining boom, mining companies left the area and many of the mines were not properly closed and mine tailings were not cleaned up. This has resulted in the contamination of soil and water sources with U and other chemicals that are by products of U mining. This is of significant importance because nearly 1/3 of the residents living on the Navajo Nation rely on obtaining water from sources that may be contaminated with U. U has detrimental effects on human health and these effects are mediated by the element's chemical toxic properties, not its radioactive properties. The classic chemotoxic effect of U is nephrotoxicity. Other heavy metals exhibit estrogenic activity, and until now, U has not been among the metals tested for estrogenic activity. Estrogen has been classified as a carcinogen, so it may be possible to consider that estrogen mimics may be carcinogens also. This study examined the effect of U on estrogen responsive endpoints in in vivo and in vitro systems. Exposure to U in drinking water in ovary intact and ovariectomized rodents demonstrate changes in biological endpoints that are indicative of estrogen exposure. These results are reduced or blocked by the antiestrogen, ICI 182, 780, suggesting involvement of the estrogen receptor (ER) in mediating U induced estrogen-like effects. Utilization of various human breast endothelial cell culture systems that have differing ER content to examine possible mechanisms of action of U stimulated estrogenic outcomes, further support the involvement of the ER, but also demonstrate implications for other receptors and signaling pathways. Collectively, results presented here suggest that U can elicit estrogen-like effects in vivo and in vitro. Furthermore, U is a putative endocrine disrupting chemical that may contribute to risk of reproductive dysfunction and cancers in populations that are exposed to U in drinking water.