Marked inhibition of testosterone biosynthesis by the hepatotoxin nodularin due to apoptosis of Leydig cells.

We previously observed that the serum testosterone level was greatly reduced in the course of diethylnitrosamine-nodularin-induced hepatocarcinogenesis in Fischer 344 male rats (Lim et al., Gastroenterological Carcinogenesis, 1999). As an extension of this observation, this study was undertaken to investigate the molecular mechanism of downregulation of testosterone and its effect on target organs in Fischer 344 male rats treated with the hepatotoxin nodularin. After treating the rats with nodularin, a marked reduction of the testosterone level was noted in both serum and testis, with an accompanying accumulation of cholesterol in serum. Reduction of serum testosterone was not due to increased degradation of testosterone in the liver but to impaired biosynthesis in the testes, reduced activities of the cholesterol side chain cleavage enzyme and 17alpha-hydroxylase, and decreased expression of the steroidogenic acute regulatory protein gene, all of which constitute rate-limiting steps for testosterone biosynthesis in the testes. Intraperitoneal injection of nodularin into rats induced cuboidal changes of glandular epithelium in ventral prostates and apoptotic changes of spermatogonium, for example, nuclear chromatin condensation, shrinkage, and detachment from Sertoli cells, which included many lysosomal granules. Leydig cells also showed evidence of chromatin condensation and significant induction of peroxisome proliferation. In conclusion, the potential causes of impaired testosterone biosynthesis might have been apoptosis of Leydig cells induced by direct toxicity of the hepatotoxin on testes or hypothalamopituitary dysfunction. Copyright 2002 Wiley-Liss, Inc.