Dose-response examination of UDP-glucuronosyltransferase inducers and their ability to increase both TGF-beta expression and thyroid follicular cell apoptosis

Exposure to certain microsomal enzyme inducers that increase UDP-glucuronos yltransferase (UDP-GT) activity decreases thyroid hormone levels, which may lead to a subsequent increase in thyroid-stimulating hormone (TSH). This e levation of serum TSH has many effects on the thyroid, including increasing thyroid follicular cell proliferation, leading to hyperplasia, While induc tion of UDP-GT activity decreases thyroid hormone levels by enhancing biotr ansformation and subsequent biliary secretion, only certain UDP-GT inducers exhibit the ability to increase serum TSH levels. For example, phenobarbit al (PB) and pregnenolone-16 alpha-carbonitrile (PCN) increase serum levels of TSH, while S-methylcholanthrene (3MC) and Aroclor 1254 (PCB) do not. Inc reased serum TSH concentration also enhances thyroid gland expression of TG F-beta(1), an anti-proliferative, pro-apoptotic protein. In a previous stud y in our laboratory, rats were treated for various times (up to 90 days) wi th PB and PCN, which increased TGF-beta(1) protein and apoptosis, The prese nt study was designed to examine the dose-response effect of TSH-increasing (PB and PCN) and nonincreasing (3MC and PCB) UDP-GT inducers on apoptosis and TGF-beta(1), PB and PCN, UDP-GT inducing compounds which increase serum TSH, increased the percentage of TGF-beta(1)-positive follicular cells and increased apoptosis, In contrast, UDP-GT inducers that did not increase TS H (3MC and PCB) did not alter cell death or TGF-beta production. These data suggest that the increase of TGF-beta by TSH may serve to regulate the gro wth of hyperplastic thyroid. (C) 1998 Society of Toxicology.