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Methyl tertiary butyl ether-induced endocrine alterations in mice are not mediated through the estrogen receptor
1Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137, USA.
Abstract:
Chronic exposure to methyl tertiary butyl ether (MTBE) altered the rodent tumor incidence of endocrine-sensitive tissues and decreased the incidence of estrogen-dependent uterine cystic hyperplasia in mice. To test the hypothesis that changes in the incidence of tumors in female B6C3F1 mice after MTBE exposure are secondary to endocrine alterations, we exposed female mice to the carcinogenic dose of MTBE vapor (8000 ppm) for 3 or 21 days or 4 or 8 months under conditions similar to a previous 2-year bioassay. MTBE exposure significantly decreased body weight gain and ovary and pituitary weight at 4 and 8 months and uterine weight at all time points. After 8 months of exposure, MTBE significantly increased the length of the estrous cycle by increasing the mean number of days in both the estrus and the nonestrus stages. Histological evaluation of H&E-stained tissues showed a decrease in the number of uterine glands after subchronic MTBE exposure. DNA synthesis, as measured by the incorporation of 5-bromo-2'-deoxyuridine (BrdU), was decreased in uterine glandular and luminal epithelial cells after MTBE exposure for 3 or 21 days or 4 or 8 months. MTBE exposure decreased the number of epithelial layers in the cervix and vagina at all time points. DNA synthesis was decreased in cervical and vaginal epithelium after 21 days of MTBE. Decreased zona reticularis of adrenal glands was found after 4 and 8 months of MTBE exposure without changes in BrdU incorporation. MTBE did not competitively bind to estrogen receptor. MTBE exposure did not alter serum estrogen levels or alter the location or intensity of estrogen receptor immunoreactivity in the uterus, cervix, and vagina. These data indicate that while MTBE exposure causes multiple endocrine-related tissue and cellular responses, these effects are not mediated through the estrogen receptor.
Insights
Chronic exposure to methyl tertiary butyl ether (MTBE) altered rodent endocrine function and decreased uterine gland number. These MTBE effects on reproductive tissues were not mediated by the estrogen receptor.
Area of Science:
- Toxicology
- Endocrinology
- Reproductive Biology
Background:
- Methyl tertiary butyl ether (MTBE) is a fuel additive with known carcinogenic potential.
- Previous studies suggest MTBE alters tumor incidence in endocrine-sensitive tissues.
- The mechanism by which MTBE affects endocrine-sensitive tissues requires further investigation.
Purpose of the Study:
- To investigate if MTBE-induced changes in female B6C3F1 mice are secondary to endocrine alterations.
- To determine the role of the estrogen receptor pathway in MTBE's effects.
Main Methods:
- Female mice were exposed to MTBE vapor (8000 ppm) for durations of 3, 21 days, 4, or 8 months.
- Evaluated body weight, organ weights (ovary, pituitary, uterus), estrous cycle length, and histological changes.
- Assessed DNA synthesis using 5-bromo-2'-deoxyuridine (BrdU) incorporation in reproductive tissues.
- Investigated estrogen receptor binding, serum estrogen levels, and receptor immunoreactivity.
Main Results:
- MTBE exposure decreased body weight gain and ovary, pituitary, and uterine weights.
- MTBE prolonged the estrous cycle and reduced uterine glands and epithelial layers in the cervix and vagina.
- DNA synthesis was decreased in uterine, cervical, and vaginal epithelial cells.
- MTBE did not competitively bind to the estrogen receptor, nor did it alter serum estrogen levels or receptor localization.
Conclusions:
- MTBE exposure induces significant endocrine-related tissue and cellular responses in female mice.
- These MTBE-induced effects are not mediated through the estrogen receptor pathway.
- Further research is needed to elucidate the specific mechanisms underlying MTBE's endocrine disruption.