2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced thymic atrophy and lymphocyte stem cell alterations by mechanisms independent of the estrogen receptor.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has both agonist and antagonist effects on estrogen-mediated activities and estrogen receptor (ER) levels in epithelial tissues following exposure. We previously demonstrated that TCDD alters bone marrow lymphocyte stem cells, including prothymocytes, as measured by functional assays and alterations in the lymphocyte stem cell-specific markers terminal deoxynucleotidyl transferase (TdT) and recombinase activating gene-1 (RAG-1). We have also shown that 17 beta-estradiol valerate (E2V) affects lymphocyte stem cells by reducing TdT and RAG-1 mRNA. It has been suggested that the effect of TCDD on these lymphocyte stem cells may be mediated directly or indirectly through estrogenic action and/or the ER. Studies were designed to evaluate whether endogenous estrogens or the ER mediate TCDD-elicited bone marrow alterations and thymic atrophy. Ovariectomy did not alter the sensitivity of mice to TCDD-induced thymic atrophy or to a reduction in TdT biosynthesis in bone marrow cells compared with either intact or sham-operated mice. The pure estrogen antagonist ICI 164,384 blocked E2V-induced uterine hypertrophy, thymic atrophy and reductions in lymphocyte stem cell markers. However, the antiestrogen failed to protect against TCDD-elicited thymic atrophy or bone marrow alterations in intact animals. The results are consistent with the hypothesis that the effects of TCDD on the thymus and/or bone marrow are mediated by mechanisms independent of estrogens or the ER.
Frazier
D E
DE
Department of Environmental Medicine, University of Rochester School of Medicine, NY 14642.
Silverstone
A E
AE
Gasiewicz
T A
TA
D000818:Animals; D001835:Body Weight; D004253:DNA Nucleotidylexotransferase / Q000096:biosynthesis; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size; D010052:Ovariectomy; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D004965:Estrogen Antagonists; D000072317:Polychlorinated Dibenzodioxins; D011960:Receptors, Estrogen; D004958:Estradiol; D004253:DNA Nucleotidylexotransferase