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Detection of Thyroid Toxicants in a Tier I Screening Battery and Alterations in Thyroid Endpoints Over 28 Days of Exposure

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Detection of Thyroid Toxicants in a Tier I Screening Battery and Alterations in Thyroid Endpoints Over 28 Days of Exposure TOXICOLOGICAL SCIENCES 51, 54–70 (1999) Copyright © 1999 by the Society of Toxicology Detection of Thyroid Toxicants in a Tier I Screening Battery and Alterations in Thyroid Endpoints over 28 Days of Exposure John C. O’Connor,1 Steven R. Frame, Leonard G. Davis, and Jon C. Cook2 DuPont Haskell Laboratory for Toxicology and Industrial Medicine, P.O. Box 50, Elkton Rd., Newark, Delaware 19714 Received February 5, 1999; accepted April 28, 1999 follicular cell proliferation (1- and 2-week time points). Histolog- Phenobarbital (PB), a thyroid hormone excretion enhancer, and ical effects in PB-treated rats were limited to mild colloid deple- propylthiouracil (PTU), a thyroid hormone-synthesis inhibitor, tion at the 2- and 4-week time points. At all three time points, PTU have been examined in a Tier I screening battery for detecting increased relative thyroid weight, increased serum TSH, decreased endocrine-active compounds (EACs). The Tier I battery incorpo- serum T3 and T4, increased thyroid follicular cell proliferation, rates two short-term in vivo tests (5-day ovariectomized female and produced thyroid gland hyperplasia/hypertrophy. Thyroid battery and 15-day intact male battery using Sprague-Dawley gland histopathology, coupled with decreased serum T4 concen- rats) and an in vitro yeast transactivation system (YTS). In addi- trations, has been proposed as the most useful criteria for identi- tion to the Tier I battery, thyroid endpoints (serum hormone fying thyroid toxicants. These data suggest that thyroid gland concentrations, liver and thyroid weights, thyroid histology, and weight, coupled with thyroid hormone analyses and thyroid his- UDP-glucuronyltransferase [UDP-GT] and 5*-deiodinase activi- tology, are the most reliable endpoints for identifying thyroid ties) have been evaluated in a 15-day dietary restriction experi- gland toxicants in a short-duration screening battery. The data ment. The purpose was to assess possible confounding of results further suggest that 2 weeks is the optimal time point for identi- due to treatment-related decreases in body weight. Finally, several fying thyroid toxicants based on the 9 endpoints examined. Hence, thyroid-related endpoints (serum hormone concentrations, hepatic the 2-week male battery currently being validated as part of this UDP-GT activity, thyroid weights, thyroid follicular cell prolifer- report should be an effective screen for detecting both potent and ation, and histopathology of the thyroid gland) have been evalu- weak thyroid toxicants. ated for their utility in detecting thyroid-modulating effects after Key Words: screening; Tier I battery; rats; thyroid gland; hor- 1, 2, or 4 weeks of treatment with PB or PTU. In the female battery, changes in thyroid endpoints following PB administra- mone concentrations; cell proliferation; UDP-glucuronyltrans- ferase; phenobarbital; propylthiouracil; time course; dietary re- tion, were limited to decreased serum tri-iodothyronine (T3) and striction. thyroxine (T4) concentrations. There were no changes in thyroid stimulating hormone (TSH) concentrations or in thyroid gland histology. In the male battery, PB administration increased serum TSH and decreased T3 and T4 concentrations. The most sensitive Under the current legislative requirements of the Food Qual- indicator of PB-induced thyroid effects in the male battery was ity Protection Act of 1996 and the Safe Drinking Water Act of thyroid histology (pale staining and/or depleted colloid). In the 1996, the United States Environmental Protection Agency female battery, PTU administration produced increases in TSH (U.S. EPA) was mandated, starting in August 1999, to imple- concentrations, decreases in T3 and T4 concentrations, and micro- scopic changes (hypertrophy/hyperplasia, colloid depletion) in the ment a testing strategy for screening chemicals and pesticides thyroid gland. In the male battery, PTU administration caused for endocrine activity. In response, the EPA established the thyroid gland hypertrophy/hyperplasia and colloid depletion, and Endocrine Disruptor Screening and Testing Advisory Commit- the expected thyroid hormonal alterations (increased TSH, and tee (EDSTAC) to provide screening strategies. Presently, the decreased serum T3 and T4 concentrations). The dietary restriction EDSTAC is recommending screening compounds for their study demonstrated that possible confounding of the data can potential to act as agonists or antagonists to the estrogen occur with the thyroid endpoints when body weight decrements receptors (ER) or androgen receptors (AR), steroid biosynthe- are 15% or greater. In the thyroid time course experiment, PB produced increased UDP-GT activity (at all time points), in- sis inhibitors, or for their ability to alter thyroid function (EDSTAC, 1998). As part of our research program to develop creased serum TSH (4-week time point), decreased serum T3 (1- and 2-week time points) and T4 (all time points), increased relative effective methods to screen for endocrine-active compounds thyroid weight (2- and 4-week time points), and increased thyroid (EACs), we have initiated a validation of a tiered-testing 1 scheme using 15 model EACs (Cook et al., 1997; O’Connor et To whom correspondence should be addressed. Fax (302) 366-5003. al., 1998a,b). Our Tier I-testing scheme incorporates two short- Email: [email protected]. 2 Present address: Pfizer, Inc., Central Research, Eastern Point Rd., Groton, term in vivo tests (5-day ovariectomized female battery; 15-day CT 06340. intact male battery) and an in vitro yeast transactivation system 54 RECOMMENDATIONS FOR SCREENING FOR THYROID TOXICANTS 55 (YTS) for identifying compounds that alter endocrine ho- Many factors can affect thyroid hormone concentrations in- meostasis. The two main goals of these studies are to test the cluding diet, stress, age, and circadian rhythm (Capen, 1997; hypothesis that distinct “fingerprints” of endocrine activity can Hill et al., 1989). Furthermore, detection of small changes in be identified for specific EACs, and to evaluate which end- thyroid hormone concentrations can be difficult due to normal points should be included in a final Tier I type screen. We have variability between animals (Davies, 1993). For these reasons, previously used 6 positive controls to examine the usefulness care must be taken in the interpretation of hormonal data to of the Tier I screening battery for identifying EACs with differentiate between changes in thyroid hormone homeostasis diverse endocrine activities (O’Connor et al., 1998a,b). In this that represent modulation (compensated changes that produce report, we examined phenobarbital (PB), a thyroid hormone- no tissue structural changes) and those that represent disruption excretion enhancer, and 6-n-propyl-2-thiouracil (propylthio- (changes that cannot be compensated for and produce tissue uracil; PTU), a thyroid hormone-synthesis inhibitor, in order to structural changes) of the thyroid axis. characterize the ability of the Tier I screening battery to detect At the 1997 Duke University Thyroid Workshop (Durham, known thyroid toxicants. NC) entitled Screening Methods for Chemicals That Alter Considerable data from studies in experimental animals in- Thyroid Hormone Action, Function and Homeostasis, thyroid dicate the existence of a relationship between sustained dis- gland histopathology was judged to be the most sensitive ruption of the hypothalamic-pituitary-thyroid (HPT) axis and parameter for the detection of compounds that adversely affect the progression of thyroid follicular cells to hypertrophy, hy- thyroid function. One concern regarding the inclusion of thy- perplasia, and eventually neoplasia (Hill et al., 1989; Paynter et roid gland histopathology is that it is unclear whether a 2-week al., 1988). In particular, hypersecretion of thyroid stimulating or even a 4-week exposure is long enough to detect weak- hormone (TSH) has been recognized as a common mechanism acting compounds that disrupt thyroid economy (i.e., com- for the induction of thyroid follicular cell proliferative lesions pounds whose primary action is in the periphery). To date, only by xenobiotics that disrupt thyroid hormone homeostasis (re- one published report has observed that PB can induce his- viewed in Capen, 1997; Davies, 1993; Hill et al., 1989). All topathological changes in the thyroid gland after 20 days of known thyroid tumorigens (except those that are direct muta- treatment (Japundzic, 1969). A comprehensive evaluation of a gens), as well as iodine deficiency, induce thyroid proliferative battery of thyroid endpoints in a single study design over 4 lesions through a chronic compensatory secretion of TSH, as a weeks of treatment has yet to be reported. result of perturbations in thyroid hormone economy (reviewed In the current study, two model thyroid toxicants, PB and in Capen, 1997; Davies, 1993; Hill et al., 1989). However, the PTU, have been examined using a Tier I screening battery. PB increased secretion of TSH may be prompted by several mech- and PTU were used to characterize the ability of our proposed anisms, such as direct action on the thyroid gland, either by Tier I screening battery to detect thyroid toxicants with differ- inhibition of thyroid hormone synthesis or secretion, or indi- ent modes of action, indirect versus direct, respectively. In rectly through inhibition of 59-deiodinase or induction of he- addition, we have examined the effect of diet restriction for 15 patic microsomal enzymes (reviewed in Capen, 1997; Leonard days
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