Toxicological Sciences 66, 62-68 (2002)
Copyright © 2002 by the Society of Toxicology
ENDOCRINE TOXICOLOGY |
Dioxin Inhibition of Estrogen-Induced Mouse Uterine Epithelial Mitogenesis Involves Changes in Cyclin and Transforming Growth Factor-ß Expression
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* Center for Integrative Bioscience, Okazaki National Research Institutes, Okazaki, Aichi 444-8585, Japan;
CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan;
National Institute for Environmental Studies, Tsukuba, 305-8506, Japan; and
Department of Veterinary Biosciences and
¶ Division of Nutritional Sciences, University of Illinois, Urbana 61802, Illinois
A single dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD; 5 µg/kg, ip) inhibits 17ß-estradiol (E2)-induced uterine epithelial mitogenesis, apparently through disruption of stromal-epithelial interactions. To understand if TCDD alters early uterine (Ut) responses to E2, young adult C57BL/6J mice were ovariectomized and given (ip) either oil or 5 µg/kg TCDD. After 24 h, TCDD-treated mice received E2, and oil-treated mice were given E2 or oil. Body and Ut weights were collected 6 and 18 h later. Ut were flash-frozen at 6 h. E2 increased Ut weight (p < 0.0001) and Ut/body weight ratio (p < 0.0001), compared to mice given oil alone. Ut cyclin expression was assessed by an RNase protection assay. E2 increased mRNA expression for cyclin A2 and B1 (p < 0.05), in addition to D1, D2, and D3 (p < 0.001), while cyclin C was unchanged from oil controls and cyclins A1 and B2 were undetectable. In contrast, TCDD completely abolished E2-induced cyclin A2, which has been associated with S phase initiation, and reduced B1 and D2 (p < 0.05). Interestingly, TCDD did not alter E2-induced Ut weight increases at 6 h, but inhibited E2-induced Ut weight gain at 18 h. A 10-µg/kg TCDD dose was necessary for attenuation of the early E2-induced Ut weight increases (p < 0.01). Since TGF-ß regulates cyclins, Ut TGF-ß was also assessed in TCDD + E2-treated and control mice. TGF-ß mRNA levels were increased after TCDD compared to E2 alone (p < 0.01), suggesting a possible mechanism for TCDD inhibition of Ut cyclin A2. Thus, TCDD alters specific E2-regulated Ut G1 phase activities and may inhibit E2-induced Ut epithelial mitogenesis by disrupting specific cell signaling mechanisms necessary for S phase initiation in vivo.
Key Words: cytokine; uterus; estrogen; proliferation; antiestrogen; aryl hydrocarbon receptor; ovariectomy.
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