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Sara E. Walker,¹ Lydia W. Keisler,² C. William Caldwell,³ Ann B. Kier,⁴ and Frederick S. vom Saal⁵

¹Rheumatology Section, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri; ²Department of Internal Medicine, University of Missouri, Columbia, Missouri; ³Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri; ⁴Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas; ⁵Department of Biological Sciences, University of Missouri, Columbia, Missouri

Abstract

F₁ hybrid New Zealand Black (NZB) New Zealand White (NZW) (NZB/NZW) mice spontaneously develop an autoimmune disease analogous to systemic lupus erythematosus (SLE) . Testosterone exerts a powerful suppressive effect on this disorder in adult NZB/NZW mice. A series of experiments was designed to determine if disease would also be suppressed by exposing fetal NZB/NZW mice to increased testosterone. A model was developed in which NZB dams carrying NZB/NZW fetuses were treated with testosterone in a dose adequate to masculinize the external genitalia in female fetuses. NZB/NZW mice that were derived from testosterone-treated dams and control NZB/NZW offspring were followed in a longevity study and had serial assays to assess development of SLE. Additional experiments were carried out to measure lymphocyte subsets and responses to mitogens. Results were compared with F₁ hybrid offspring of C57BL/6 dams crossed with DBA/2 males, which are not autoimmune and do not develop SLE. Spleen cells from these groups were tested for Thy 1.2, CD4, CD8, and IgM receptors, and for responses to the mitogens Concanavalin A (ConA) and lipopolysaccharide. Control male NZB/NZW fetuses had unexpectedly high serum estradiol, which decreased significantly with maternal testosterone treatment. The testosterone-exposed male NZB/NZW fetuses developed into adults that lived longer than male NZB/NZW controls. Testosterone treatment of the dam was associated with elevated terminal anti-DNA levels but did not alter markers of renal disease in adult NZB/NZW mice of either sex. Testosterone-exposed NZB/NZW females had altered T-lymphocyte subsets and testosterone-exposed males had increased response to ConA compared to controls. In male NZB/NZW fetuses whose mothers were administered testosterone, the naturally high level of circulating estradiol observed in untreated male fetuses was decreased significantly. This decrease was associated with an increase in longevity. This unique observation has important implications for fetal exposure to endocrine disruptors in the environment. -- Environ Health Perspect 104(Suppl 4) :815-821 (1996)

Key words: autoimmunity, NZB mouse, C57BL/6 mouse, fetus, testosterone, estradiol, longevity