Immunomodulation by diethylstilbestrol is dose and gender related: effects on thymocyte apoptosis and mitogen-induced proliferation.
It is believed, but not proven, that the immunomodulatory effects of DES may vary with the dose and/or gender. To address these critical gaps in the literature, diethylstilbestrol (DES) was administered to female and male CD-1 mice as four subcutaneous injections for 1 week at 0, 5, 15, and 30 microg/kg bw doses, and immunological and reproductive effects examined a day after the last injection. Female thymuses were significantly larger than their male counterparts. Short-term administration of DES to female or male mice neither induced thymic atrophy nor altered the relative percentages of thymic subsets. Nevertheless, DES treatment of female or male mice induced a dose-related apoptosis of CD4(+)8(+), CD4(+)8(-) and CD4(-)8(+) subsets as analyzed by 7-amino-actinomycin D (7-AAD). Immature CD4(-)8(-) subset of thymocytes from females was also affected by high dose DES. The pattern of mitogen-induced proliferation of splenic lymphocytes varied with the dose of hormone and the gender. In females, splenic lymphocytes from low dose DES (5 microg/kg bw)-treated mice exhibited an increased proliferative response to Con-A, LPS or PMA/ionomycin compared with controls. Similar cultures from mice treated with higher doses of DES (15 or 30 microg/kg bw) did not manifest an increased proliferative response, but rather showed a trend for suppressed proliferation, especially in response to Con-A. In males, DES had minimal effects with the exception of increased proliferative response to Con-A in splenocytes from medium-dose-DES-treated mice. The changes in mitogen-induced proliferation in DES-treated female mice were not mirrored by similar changes in the relative numbers of CD90(+) or CD45R(+) cells, or in ratios of anti-apoptotic Bcl-2 to apoptotic Bax proteins. Con-A-activated splenocytes from DES-treated mice, particularly from females, had a decreased ability to secrete interferon-gamma compared with controls. Taken together, these findings suggest that short-term exposure to DES has differential immunological effects depending upon the dose of hormone and sex.
Calemine
J B
JB
Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg 24061-0342, USA.
Gogal
R M
RM
Lengi
A
A
Sponenberg
P
P
Ahmed
S Ansar
SA
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005835:Genitalia / Q000187:drug effects / Q000254:growth & development; D008221:Lymphoid Tissue / Q000187:drug effects; D008297:Male; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D012098:Reproduction / Q000187:drug effects; D012727:Sex Characteristics; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects*; D013950:Thymus Gland / Q000187:drug effects
D000276:Adjuvants, Immunologic; D016207:Cytokines; D004968:Estrogens, Non-Steroidal; D008934:Mitogens; D004054:Diethylstilbestrol