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Description
Methyl-t-butyl ether (MTBE) is used as a gasoline additive to improve motor vehicle combustion and to reduce emissions of some pollutants. Exposure via inhalation has been a major concern for public health due to its use as a fuel additive; however it has currently been found as a contaminant in ground water and surface waters used for drinking due to gasoline leaking from underground fuel-storage tanks. Although now completely or partially banned for use in fuel in the United States, contamination of water resources has intensified the public's concern for MTBE health risks and has raised new issues about MTBE impacts. Long-term, low-dose effects on humans are unknown at this time. Extensive research has been conducted in rodents, including long-term cancer bioassays using high concentrations of MTBE—at much higher concentrations than levels found in nature. Several studies on rodents exposed to high concentrations of MTBE have shown cancer at different organ sites in both females and males. Statistically significant increases in lymphomas and leukemia (combined) in females were found along with liver cancer. Also in male Sprague-Dawley rats receiving MTBE by gavage, statistically significant increases in Leydig interstitial cell tumors of the testes were observed. Induction of total liver cytochrome P450 and specific isozymes has also been noted. This thesis was conducted to provide a better understanding of how MTBE causes the types of tumors reported at high doses in rodent models in lifetime cancer bioassays. An underlying hypothesis of most of these models is that MTBE disrupts normal reproductive endocrine function resulting in an abnormal balance of testosterone and estradiol. The primary area of interest in this study is estrogen synthase, most commonly known as "aromatase." Aromatase can be found in the smooth endoplasmic reticulum of most organs in the body and is primarily responsible for the conversion of androgens to estrogens via a specific P450 isozyme (CYP19). It was found that high doses of MTBE reduce circulating levels of testosterone. In addition, a 14 day study in male rats also documented an increase in the activity of cytochrome P450 enzyme (CYP19 or aromatase) that is involved in the conversion of testosterone to estradiol. If aromatase is involved in the steroidogenic pathway of male rats and has been proven to affect female mice, then we would expect to see an effect of these steroid hormones in female rats as well. Adult Sprague-Dawley female rats were gavaged with 1200 MTBE mg/Kg/day for fourteen consecutive days. This study focused specifically on detecting reproductive steroid hormone imbalance, and levels of liver and ovarian aromatase mRNA transcripts. Enzyme immunoassays were used for testosterone and estradiol measurement. Only small changes were observed in the MTBE treated group. No statistically significant changes were found in estradiol, testosterone, or aromatase mRNA. A dose-related decrease in serum AST, BUN and creatinine was observed; however, these effects were not statistically significant (P>0.05). Results suggested that MTBE did not directly affect the sterodoigenic pathway
