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Differential effects of diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocyte differentiation, proliferation, and apoptosis in bcl-2 transgenic mouse fetal thymus organ culture.
Toxicol Appl Pharmacol. 2000 Oct 01; 168(1):15-24.TA

Abstract

Both the estrogenic drug diethylstilbestrol (DES) and the pervasive environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibit thymocyte development. The mechanisms by which either agent induces thymic atrophy are still undetermined. We previously found that TCDD and DES inhibited C57BL/6 murine fetal thymocyte organ cultures (FTOC) at different stages of development. Now, using bcl-2 transgenic (TG) mice, we have further investigated their effects on FTOC proliferation, differentiation, maturation, and apoptosis. As with C57BL/6 mice, thymocyte development in C3H/bcl-2 FTOCs was inhibited by either TCDD (10 nM) or DES (20 microM) in both bcl-2 TG- and TG+ littermates. However, the percentage reduction of cell number induced by DES in bcl-2 TG+ FTOCs was significantly less than the level of inhibition in TG- FTOCs. There was no difference in the level of reduction from TCDD-exposed TG+ or TG- FTOC. Whereas TCDD increased production of mature CD8 cells in either strain, DES mainly yielded cells in the CD4(-)CD8(-)(DN) stage in TG- mice. The anti-apoptotic bcl-2 transgene overcame some DES blocking of DN thymocyte development, allowing more cells to differentiate into CD4 single-positive cells. Analysis of cell cycle showed that TCDD inhibited entry into S phase, whereas DES blocked cell cycling in the G2/M phase. TCDD did not induce detectable apoptosis in FTOC. However, unlike the effects of 17 beta-estradiol (E2) in vivo, DES induced apoptosis in the TG- FTOC, and these apoptotic cells were mainly in the DN subpopulation. This apoptosis could be prevented by the overexpression of bcl-2 in the TG+ mice. Our results demonstrate that, in addition to inhibition of fetal thymocytes at different stages of development by TCDD and DES, DES also induces thymic atrophy by both bcl-2-inhibitable apoptosis and by inducing cell cycle arrest in G2/M in the latest stage in the stem cell compartment. TCDD, on the other hand, does not induce apoptosis, but inhibits entry into cell cycle in the earliest stage in the stem cell compartment.

Authors+Show Affiliations

Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11000096

Citation

Lai, Z W., et al. "Differential Effects of Diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin On Thymocyte Differentiation, Proliferation, and Apoptosis in Bcl-2 Transgenic Mouse Fetal Thymus Organ Culture." Toxicology and Applied Pharmacology, vol. 168, no. 1, 2000, pp. 15-24.
Lai ZW, Fiore NC, Hahn PJ, et al. Differential effects of diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocyte differentiation, proliferation, and apoptosis in bcl-2 transgenic mouse fetal thymus organ culture. Toxicol Appl Pharmacol. 2000;168(1):15-24.
Lai, Z. W., Fiore, N. C., Hahn, P. J., Gasiewicz, T. A., & Silverstone, A. E. (2000). Differential effects of diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocyte differentiation, proliferation, and apoptosis in bcl-2 transgenic mouse fetal thymus organ culture. Toxicology and Applied Pharmacology, 168(1), 15-24.
Lai ZW, et al. Differential Effects of Diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin On Thymocyte Differentiation, Proliferation, and Apoptosis in Bcl-2 Transgenic Mouse Fetal Thymus Organ Culture. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):15-24. PubMed PMID: 11000096.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocyte differentiation, proliferation, and apoptosis in bcl-2 transgenic mouse fetal thymus organ culture. AU - Lai,Z W, AU - Fiore,N C, AU - Hahn,P J, AU - Gasiewicz,T A, AU - Silverstone,A E, PY - 2000/9/23/pubmed PY - 2001/2/28/medline PY - 2000/9/23/entrez SP - 15 EP - 24 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 168 IS - 1 N2 - Both the estrogenic drug diethylstilbestrol (DES) and the pervasive environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibit thymocyte development. The mechanisms by which either agent induces thymic atrophy are still undetermined. We previously found that TCDD and DES inhibited C57BL/6 murine fetal thymocyte organ cultures (FTOC) at different stages of development. Now, using bcl-2 transgenic (TG) mice, we have further investigated their effects on FTOC proliferation, differentiation, maturation, and apoptosis. As with C57BL/6 mice, thymocyte development in C3H/bcl-2 FTOCs was inhibited by either TCDD (10 nM) or DES (20 microM) in both bcl-2 TG- and TG+ littermates. However, the percentage reduction of cell number induced by DES in bcl-2 TG+ FTOCs was significantly less than the level of inhibition in TG- FTOCs. There was no difference in the level of reduction from TCDD-exposed TG+ or TG- FTOC. Whereas TCDD increased production of mature CD8 cells in either strain, DES mainly yielded cells in the CD4(-)CD8(-)(DN) stage in TG- mice. The anti-apoptotic bcl-2 transgene overcame some DES blocking of DN thymocyte development, allowing more cells to differentiate into CD4 single-positive cells. Analysis of cell cycle showed that TCDD inhibited entry into S phase, whereas DES blocked cell cycling in the G2/M phase. TCDD did not induce detectable apoptosis in FTOC. However, unlike the effects of 17 beta-estradiol (E2) in vivo, DES induced apoptosis in the TG- FTOC, and these apoptotic cells were mainly in the DN subpopulation. This apoptosis could be prevented by the overexpression of bcl-2 in the TG+ mice. Our results demonstrate that, in addition to inhibition of fetal thymocytes at different stages of development by TCDD and DES, DES also induces thymic atrophy by both bcl-2-inhibitable apoptosis and by inducing cell cycle arrest in G2/M in the latest stage in the stem cell compartment. TCDD, on the other hand, does not induce apoptosis, but inhibits entry into cell cycle in the earliest stage in the stem cell compartment. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/11000096/Differential_effects_of_diethylstilbestrol_and_2378_tetrachlorodibenzo_p_dioxin_on_thymocyte_differentiation_proliferation_and_apoptosis_in_bcl_2_transgenic_mouse_fetal_thymus_organ_culture_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(00)99015-X DB - PRIME DP - Unbound Medicine ER -