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 antago nist effects on estrogen-mediated activities and estrogen receptor (ER ) levels in epithelial tissues following exposure. We previously demon strated 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 trans ferase (TdT) and recombinase activating gene-1 (RAG-1). We have also s hown that 17 beta-estradiol valerate (E(2)V) affects lymphocyte stem c ells by reducing TdT and RAG-1 mRNA. It has been suggested that the ef fect of TCDD on these lymphocyte stem cells may be mediated directly o r indirectly through estrogenic action and/or the ER. Studies were des igned to evaluate whether endogenous estrogens or the ER mediate TCDD- elicited bone marrow alterations and thymic atrophy. Ovariectomy did n ot alter the sensitivity of mice to TCDD-induced thymic atrophy or to a reduction in TdT biosynthesis in bone marrow cells compared with eit her intact or sham-operated mice. The pure estrogen antagonist ICI 164 ,384 blocked E(2)V-induced uterine hypertrophy, thymic atrophy and red uctions in lymphocyte stem cell markers. However, the antiestrogen fai led to protect against TCDD-elicited thymic atrophy or bone marrow alt erations in intact animals. The results are consistent with the hypoth esis that the effects of TCDD on the thymus and/or bone marrow are med iated by mechanisms independent of estrogens or the ER.