PEROXISOME PROLIFERATORS ALTER THE EXPRESSION OF ESTROGEN-METABOLIZING ENZYMES

Exposure to some peroxisome proliferator chemicals (PPC) leads to toxi c effects on sex organ function possibly by alterations of steroid hor mone metabolism. A systematic search for genes whose mRNA levels are m odulated by the PPC WY-14643 (WY) was carried out in rat liver, a site of steroid hormone metabolism. The sequence of one up-regulated cDNA (2480 bp) was predicted to encode a protein of 735 amino acids with 82 % identity to the porcine 17 beta-hydroxysteroid dehydrogenase type Iv (HSD IV) originally isolated as a 17 beta-estradiol dehydrogenase. Th e rat HSD IV was localized to peroxisomes and was regulated by diverse PPC by two distinct mechanisms. Induction of HSD IV and acyl-CoA oxid ase (AGO) proteins in rat liver at different treatment times and conce ntrations of gemfibrozil (GEM) and di-n-butyl phthalate (DBP) were alm ost identical, suggesting that HSD IV mRNA induction involves the pero xisome proliferator-activated receptor cr, a regulator of AGO. In cont rast, HSD IV protein levels were only weakly induced by WY, a strong i nducer of ACO protein, even though the levels of both HSD IV and ACO m RNA were strongly stimulated by WY. Thus HSD IV protein levels were un iquely regulated pretranslationally by WY. In addition to HSD IV we al so identified the male-specific alpha(2u)-globulin as a PPC down-regul ated gene. This prompted us to examine the expression of another male- specific gene, CYP2C11, that catalyzes the hydroxylations of estradiol at the 2 and 16 alpha positions. Cyp2C11 protein expression in rat li ver was either decreased or completely abolished after a 3-week treatm ent by GEM or WY, respectively. Decreased expression of enzymes which inactivate estradiol including Cyp2C11, and the reported increased exp ression of aromatase may explain why male rats exposed to diverse PPC have higher serum estradiol levels. These higher estradiol levels in m ale rats have been thought to be mechanistically linked to Leydig cell hyperplasia and adenomas. Increased conversion of estradiol to the le ss active estrone by HSD IV induction may explain how exposure to the phthalate di-(2-ethylhexyl) phthalate leads to decreases in serum estr adiol levels and suppression of ovulation in female rats.