In Vivo Regulation of Steroid Hormones by the Chst10 Sulfotransferase in Mouse

Chst10 adds sulfate to glucuronic acid to form a carbohydrate antigen, HNK-1, in glycoproteins and glycolipids. To determine the role of Chst10 in vivo, we generated systemic Chst10-deficient mutant mice. Although Chst10−/− mice were born and grew to adulthood with no gross defects, they were subfertile. Uteri from Chst10−/− females at the pro-estrus stage were larger than those from wild-type females and exhibited a thick uterine endometrium. Serum estrogen levels in Chst10−/− females were higher than those from wild-type females, suggesting impaired down-regulation of estrogen. Because steroid hormones are often conjugated to glucuronic acid, we hypothesized that Chst10 sulfates glucuronidated steroid hormone to regulate steroid hormone in vivo. Enzymatic activity assays and structural analysis of Chst10 products by HPLC and mass spectrometry revealed that Chst10 indeed sulfates glucuronidated estrogen, testosterone, and other steroid hormones. We also identified an HPLC peak corresponding to sulfated and glucuronidated estradiol in serum from wild-type but not from Chst10 null female mice. Estrogen-response element reporter assays revealed that Chst10-modified estrogen likely did not bind to its receptor. These results suggest that subfertility exhibited by female mice following Chst10 loss results from dysregulation of estrogen. Given that Chst10 transfers sulfates to several steroid hormones, Chst10 likely functions in widespread regulation of steroid hormones in vivo.Background: Chst10 transfers sulfate to glucuronic acid to form the HNK-1 antigen carried by glycoproteins and glycolipids in neurons and NK cells.Results: Chst10 transfers sulfate to glucuronidated steroid hormones, and Chst10-deficient mice exhibited subfertility.Conclusion: Subfertility in Chst10 null females is caused by a loss of steroid hormone dysregulation.Significance: This study identified a new regulatory mechanism mediated by sulfation of glucuronidated steroid.