Immunomodulation by diethylstilbestrol is dose and gender related: effects on thymocyte apoptosis and mitogen-induced proliferation

• Published in: Toxicology (Amsterdam) 2002-09, Vol.178 (2), p.101-118
• Main Authors: Calemine, J.B, Gogal, R.M, Lengi, A, Sponenberg, P, Ahmed, S.Ansar
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; B-Lymphocytes - drug effects; Biological and medical sciences; Blotting, Western; Body Weight - drug effects; Cell Division - drug effects; Cytokines - metabolism; Diethylstilbestrol (DES); Diethylstilbestrol - pharmacology; Dose; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Estrogens, Non-Steroidal - pharmacology; Female; Flow Cytometry; Gender; Genitalia - drug effects; Genitalia - growth & development; Immunity; Lymphoid Tissue - drug effects; Male; Medical sciences; Mice; Miscellaneous (drug allergy, mutagens, teratogens...); Mitogens - pharmacology; Organ Size - drug effects; Pharmacology. Drug treatments; Proliferation; Reproduction - drug effects; Sex Characteristics; Spleen - cytology; T-Lymphocytes - drug effects; Thymus Gland - drug effects
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(02)00201-9

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 μg/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 μg/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 μg/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-γ 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.