TISSUE-SPECIFIC INDUCTION OF 17-BETA-HYDROXYSTEROID-DEHYDROGENASE TYPE-IV BY PEROXISOME PROLIFERATOR CHEMICALS IS DEPENDENT ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA

The 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) family of prote ins regulates the levels of the active 17 beta-hydroxy forms of sex st eroids. The expression of 17 beta-HSD type IV is induced by peroxisome proliferator chemicals (PPC) in rat liver. In order to characterize m ore generally the impact of PPC oil 17 beta-HSD expression, we determi ned (1) if expression of other members of the 17 beta-HSD family was c oordinately induced by PPC exposure, (2) the tissues in which 17 beta- HSD was induced by PPC, and (3) whether the induction of 17 beta-HSD b y PPC was dependent on the peroxisome proliferator-activated receptor alpha (PPAR alpha), the central mediator of PPC effects in the mouse l iver. The mRNA levels of 17 beta-HSD I, II, and III were not altered i n the liver, kidney, and testis or uterus of rats treated with PPC. Th e mRNA or 80 kDa full-length protein levels of 17 beta-HSD IV were str ongly induced in liver and kidney, but not induced in adrenals, brown fat, heart, testis, and uterus of rats treated with diverse PPC. In li ver and kidneys from treated rats, additional proteins of 66 kDa, 56 k Da, and 32 kDa were also induced which reacted with the anti-17 beta-H SD IV antibodies and were most likely proteolytic fragments of 17 beta -HSD IV. Treatment of mice which lack a functional form of PPAR alpha with PPC, demonstrated that PPC-inducibility of 17 beta-HSD IV mRNA or the 80 kDa protein was dependent on PPAR alpha expression in Liver an d kidney. Our results demonstrate that 17 beta-HSD IV is induced by PP C through a PPAR alpha dependent mechanism and support the hypothesis that exposure to PPC leads to alterations in sex steroid metabolism.