The long term objective of our research is to understand the basis of diethylstilbestrol (DES) and cadmium(Cd) toxicities in the ventral prostate (VP) of young and old testosterone (T)-supported rats. We and others have shown that the VP exhibits unique susceptibilities to these toxicants. Our preliminary data revealed that both T+DES- and Cd- treatment of rats induced severe oxidative stress (OS) as well as aberrant proliferative and apoptotic activities in this prostatic lobe. T+DES and Cd separately induced VP tumors in life-time studies, and synergistically early dysplastic changes. We found that the VP expresses minimal levels of mRNA of metallothioneins (MTs) which are heavy metal binding proteins believed to function as intracellular metal-ion chelators and/or antioxidants. We recently reported marked increases in lipid peroxidation status and drastic decline in the activities of reactive oxygen species (ROS) detoxification enzymes in the VPs of aged rats. Taken together, we hypothesize that T+DES and Cd are potent carcinogens for rat VP because, inter alia, they exacerbate oxidative stress (OS) in the aging VP. We thus postulate that 1) induction of OS and associated events, such as DNA single-strand breaks and apoptosis- cell proliferation imbalance, are early events leading to T+DES- and/or Cd-induced dysplasia and cancer development in rat VP, and 2) the VP of an aged rat is more susceptible to tumor induction by these toxicants than its younger littermates. Experiments have been designed to determine whether l) T+DES and/or Cd induce OS, DNA damage, and imbalance in cell proliferation-apoptosis in the VP and these events precede the development of dysplasia 2) these OS-inducers activate MT gene expression 3) the aged VPs have reduced ROS detoxification capability and thus are more sensitive to T+DES and/or Cd action 4) T+DES and Cd, given simultaneously to rats, have compounded effects on OS, dysplasia, and tumor induction in the VP and 5) T+DES with and without Cd can induce OS parameters in organ cultures of VP of young and aged rats and, if so, whether antioxidants added in vitro can reverse these damages. Results form this work will enhance our understanding of aging and OS in toxicant- induced carcinogenesis and the potential application of antioxidants as anti-cancer chemopreventive measures.

R01AG013965

1997-03-20

2003-02-28