This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. BDO2, the most active metabolite of 1,3-BD a potential human carcinogen is released into the environment as a result of petroleum byproduct, smoking or combustion of gasoline products. Once in ambient air its readily enters the body by several routs such as inhalation or absorption through the skin where it is metabolized to a BDO2 by cytochrome P450s. In the body, BDO2 may induce reproductive toxicity in target tissue such as ovaries, testis, and prostate. However, the biochemical mechanism of BDO2 toxicity in prostate and BDO2's effects on prostate cell function is undefined. Therefore, the objective of this study was to define some of the cellular changes that are associated with BDO2 toxicity in prostate cells under androgen sensitive (LNCaP(AR+)) and androgen insensitive DU-145 (DU145(AR-)) status. We observed that micro-doses of BDO2 resulted in a dose- and time-dependent decreases in PSA secretion by LNCaP cells and increases expression of prostate tumor marker in LNCaP(AR+) and DU145(AR-) cells. BDO2 induces a higher decrees of cytotoxicity in DU145(AR-) cells as compared to LNCaP(AR+) at the micro-doses examined. The increases sensitive of DU145(AR-) cells to BDO2 toxicity is likely due to the absence of AR since transient transfection of AR into theses cell reverses the BDO2 sensitivity. Exposure of prostate cells to micro-doses of BDO2 increases apoptosis, which correlates with increases caspases and Bcl2 protein and mRNA levels. In cell DU145(AR-) cell transient transfection with AR, the levels of cytotoxicity and caspases activity was decreased in the presence of BDO2 but BDO2 induce apoptotic proteins expression was unaltered. This study provides evident that micro-doses of BDO2 modulates prostate cell toxicity by promoting apoptosis and tumor gene expression.
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