Evaluate the levels of the AHR and ARNT in the female reproductive tract. RESULTS Emerging evidence suggests that environmental contaminants such as dioxin can act as endocrine disrupters through inappropriate modulation of target responses to hormones. These compounds produce their biological and toxicological effects by binding to the AHR. Binding of AHR by agonists like dioxin initiates a series of events resulting in dissociation of hsp90, movement into the nuclear compartment and heterodimerization with another protein termed ARNT. The resulting AHR-ARNT complex binds to cis-acting DNA sequences called dioxin-response elements to modulate transcription of a number of genes such as drug metabolizing enzymes, estrogen receptor, and growth factors like IL-I?, TGF-? and TGF-?. The goal of this study was to characterize the expression of AHR/ARNT in reproductive tissues were obtained from women undergoing total hysterectomy and bilateral salpingoophorectomy for benign gynecologic disease. Ribonuclease protection assay (RPA) was used to quantify the AHR and ARNT mRNA levels. Immunohistochemistry using polyclonal antibodies to AHR and ARNT were used to determine the tissue localization of these proteins. AHR and ARNT mRNA were readily detectable in the endometrium, myometrium, ovary, fallopian tube and placenta. The highest expression of mRNA for AHR/ARNT was found in the fallopian tube followed by the placenta, ovary and uterine tissues. IHC revealed both AHR and ARNT were present predominantly in the endometrial glands in the basiglandular areas and lumina1 surface of the epithelium In the myometrium a diffuse distribution in the myocytes, and in tunica media of spiral arterioles was found. A statistically significant variation in endometrial AHR and ARNT mRNA was not found during the menstrual cycle, although there was a trend for higher AHR expression in the proliferative phase and in specimens with adenomyosis (P=0.1). Greater expression of AHR was found in the endometrium of postmenopausal women treated with continuous hormone replac ement therapy as compared to women on no hormones (P=0.01). The differential tissue specific expression of AHR/ARNT in the reproductive tract suggests a physiologic role for these proteins in reproductive processes, and in pathologic procosses such as adenomyosis. Exogenous sex steroids upregulate AHR but not ARNT in the endometrium. FUTURE DIRECTIONS To extend these studies to rhesus monkeys undergoing experimental manipulation of the uterine environment with steroid hormones, and to evaluate localization at the maternal-fetal interface. KEY WORDS Aryl hydrocarbon receptor, dioxin, uterus, endometrium FUNDING RR00167, ES09090, HD34215

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000167-41
Application #
6454343
Study Section
Project Start
2001-05-01
Project End
2002-04-30
Budget Start
Budget End
Support Year
41
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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