EFFECTS OF ALTERED PRENATAL HORMONAL ENVIRONMENT ON EXPRESSION OF AUTOIMMUNE-DISEASE IN NZB NZW MICE/

F-1 hybrid New Zealand Black (NZB) x New Zealand White (NZW) (NZB/NZW) mice spontaneously develop an autoimmune disease analogous to systemi c lupus enythematosus (SLE). Testosterone exerts a powerful suppressiv e effect on this disorder in adult NZB/NZW mice. A series of experimen ts was designed to determine if disease would also be suppressed by ex posing fetal NZB/NZW mice to increased testosterone. A model was devel oped in which NZB dams carrying NZB/NZW fetuses were treated with test osterone in a dose adequate to masculinize the external genitalia in f emale fetuses. NZB/NZW mice that were derived from testosterone-treate d dams and control NZB/NZW offspring were followed in a longevity stud y and had serial assays to assess development of SLE. Additional exper iments were carried out to measure lymphocyte subsets and responses to mitogens. Results were compared with F-1 hybrid offspring of C57BL/6 dams crossed with DBA/2 males, which are not autoimmune and do not dev elop SLE. Spleen cells from these groups were tested for Thy 1.2, CD4, CD8, and IgM receptors, and for responses to the mitogens Concanavali n A (ConA) and lipopolysaccharide. Control male NZB/NZW fetuses had un expectedly high serum estradiol, which decreased significantly with ma ternal testosterone treatment. The testosterone-exposed male NZB/NZW f etuses developed into adults that lived longer than male NZB/NZW contr ols. Testosterone treatment of the dam was associated with elevated te rminal anti-DNA levels but did not alter markers of renal disease in a dult NZB/NLW mice of either sex. Testosterone-exposed NZB/NZW females had altered T-lymphocyte subsets and testosterone-exposed males had in creased response to ConA compared to controls. In male NZB/NZW fetuses whose mothers were administered testosterone, the naturally high leve l of circulating estradiol observed in untreated male fetuses was decr eased significantly. This decrease was associated with an increase in longevity. This unique observation has important implications for feta l exposure to endocrine disrupters in the environment.