The UDP-glucuronyltransferase inducers, phenobarbital and pregnenolone-16 alpha-carbonitrile, enhance thyroid-follicular cell apoptosis: association with TGF-beta(1) expression

Exposure to certain UDP-glucuronosyltransferase (UDP-GT) inducers leads to follicular cell hyperplasia, and ultimately thyroid gland tumors. These com pounds decrease thyroid hormones, which increases serum concentrations of t hyroid stimulating hormone (TSH). This induction of TSH enhances thyroid-fo llicular cell proliferation. In addition, treatment with classical goitroge nic compounds, such as propylthiouracil (PTU) and methimazole (MMI), induce s TGF-beta(1) in thyroid-follicular cells, presumably through increased TSH . In other tissues, increases in TGF-beta(1) induce apoptosis, a particular form of programmed cell death. In this experiment, we sought to determine whether the UDP-GT inducers, phenobarbital (PB) and pregnenolone-16 alpha-c arbonitrile (PCN) modulate thyroid-follicular cell apoptosis. If so, are th e induction of apoptosis and TGF-beta(1) possibly linked? An additional gro up of rats treated with the thyroid goitrogen, PTU was included. Male Sprag ue-Dawley rats were treated with thyroid hormone disrupting doses of PB, PC N, or PTU for 3, 7, 14, 21, 28, 45, or 90 days. In this study, PTU treatmen t increased apoptosis and TGF-beta(1) immunoreactive thyroid-follicular cel ls. PTU treatment of rats produced both a large increase number of TGF-beta (1)-positive cells (detected by immunohistochemistry), and apoptotic thyroi d-follicular cells (detected by morphology). In PB- and PCN-treated rats, a moderate increase in apoptosis coincided with similar increases in TGF-bet a(1) immunoreactive thyroid-follicular cells. In summary, PB and PCN increa se apoptosis and the percentage of TCF-beta(1) positive thyroid-follicular cells. Thus, treatment with UDP-GT-inducing chemicals may increase the expr ession of TGF-beta(1) and apoptosis in the thyroid to compensate for the th yroid hypertrophy and hyperplasia. (C) 1999 Elsevier Science Ireland Ltd. A ll rights reserved.