EXTRATHYROIDALLY MEDIATED CHANGES IN CIRCULATING THYROID-HORMONE CONCENTRATIONS IN THE MALE-RAT FOLLOWING ADMINISTRATION OF AN EXPERIMENTALOXYACETAMIDE (FOE-5043)

Evidence of increased hepatic metabolizing capacity coupled with reduc tions in serum thyroxine (T-4) levels were noted in the rat during pre liminary toxicity studies with FOE 5043, an oxyacetamide with herbicid al properties. These findings were consistent with reports in the lite rature suggesting that declines in T-4 as a result of exposure to vari ous classes of chemicals may be mediated extrathyroidally, such as thr ough chemical induction of hepatic thyroid hormone metabolism. To exam ine this question with respect to FOE 5043, male rats were surgically thyroidectomized and provided thyroid hormone replacement therapy via implanted osmotic minipumps capable of maintaining a T-4/triiodothyron ine (T-3) serum concentration for similar to 4 weeks at a level compar able to that of euthyroid controls. Seven days after minipump implanta tion, thyroidectomized + T-4/T-3 (TX + T-4/T-3) and nonthyroidectomize d intact rats (NTX) were fed diets containing 0, 25, 1000, or 3000 ppm FOE 5043 for up to 3 weeks. Dose-related and equivalent declines in t otal and free serum T-4 levels in both TX + T-4/T-3 and NTX rats were measured at Weeks 1, 2, and 3. Alterations in thyrotropin, total, free , and reverse serum T-3 levels were also noted in both TX and NTX anim als; however, a compound-related trend was difficult to discern and, w hen compared to the T-4 response, the changes were markedly less consi stent with respect to both time and dose. Additionally, dose-related i ncreases in absolute and relative liver weights were measured in both TX + T-4/T-3 and NTX animals. As the only source of thyroid hormone in the TX + T-4/T-3 animals was that provided by the pump, these data su ggest that FOE 5043-induced alterations in serum thyroid hormone level s, most notably T-4, are being mediated indirectly, possibly as a resu lt of increased hepatic metabolism, rather than through a direct effec t on the thyroid gland. (C) 1995 Academic Press, Inc.