Comparison of enhancing effects of different goitrogen treatments in combination with β‐estradiol‐3‐benzoate for establishing a rat two‐stage thyroid carcinogenesis model to detect modifying effects of estrogenic compounds

Abstract

With the aim of establishing a sensitive model for the detection of weak effects of endocrine disrupting chemicals on thyroid carcinogenesis, thyrotrophic and tumor-promoting influences of beta-estradiol-3-benzoate (EB) in combination with representative antithyroidal agents (goitrogens), sulfadimethoxine (SDM), propylthiouracil (PTU), potassium perchlorate (PPC), iopanoic acid (IOP) or an iodine-deficient diet were evaluated in a short-term (7-day) experiment without N-bis(2-hydroxypropyl)nitrosamine (DHPN) initiation and a long-term (30-week) experiment with DHPN initiation in ovariectomized F344 rats. In the short-term experiment, the most remarkable thyrotrophic effects were found in the PTU-treated group, followed by the SDM and PPC cases. EB treatment alone caused slight increases in thyroidal weights but no apparent morphological changes. Concomitant treatment with EB and antithyroidal agents enhanced the changes in thyroid weights, histopathological findings and/or serum thyroid hormone levels in the SDM (30 and 100 p.p.m), PTU (5 and 30 p.p.m) and PPC (100 p.p.m), IOP (30 and 100 mg/kg) or iodine-deficient diet groups. In the long-term experiment after DHPN initiation, EB alone slightly increased small numbers of animals with follicular hyperplasias, adenomas and adenocarcinomas. Simultaneous treatment with antithyroidal chemicals was associated with an increase in the incidences of focal hyperplasias, adenomas and/or adenocarcinomas. The enhancement was most remarkable with PTU (5 p.p.m), followed by PTU (2 p.p.m), SDM (100 p.p.m) and PPC (100 p.p.m). The results showed that EB has only a marginal promoting effect on DHPN-induced rat thyroid carcinogenesis and that antithyroidal chemicals, particularly PTU, are effective as co-promoting agents.