Evaluation of ammonium perchlorate in the endocrine disruptor screening and testing program's male pubertal protocol: ability to detect effects on thyroid endpoints.
The U.S. EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 male pubertal protocol was designed as a screen to detect endocrine-disrupting chemicals which may alter reproductive development or thyroid function. One purpose of this in vivo screening protocol is to detect thyrotoxicants via a number of different mechanisms of action, such as thyroid hormone synthesis or clearance. Here we evaluate the ability of this EDSP male pubertal protocol to detect the known thyrotoxicant ammonium perchlorate as an endocrine disruptor. Ammonium perchlorate is a primary ingredient in rocket fuel, fertilizers, paints, and lubricants. Over the past 50 years, potassium perchlorate has been used to treat hyperthyroidism in humans. Perchlorate alters thyroid hormone secretion by competitively inhibiting iodide uptake by the thyroid gland. In this study, ammonium perchlorate was administered at 62.5, 125, 250, and 500 mg/kg to male Wistar rats based on a pilot study of oral dosing. Doses of 125-500 mg/kg perchlorate decreased T4 in a dose-dependent manner. TSH was significantly increased in a dose-responsive manner at the same doses, while T3 was unchanged at any dose. Thyroid histology was significantly altered at all doses, even at the 62.5 mg/kg, with a clear dose-dependent decrease in colloid area and increase in follicular cell height. No effects on preputial separation, a marker of pubertal progression, or reproductive tract development were observed at any dose. These results demonstrate that the male pubertal protocol is useful for detecting thyrotoxicants which target the thyroid axis by this mechanism (altered uptake of iodide). This study also found that perchlorate exposure during this period did not alter any of the reproductive developmental endpoints.
Stoker
T E
TE
Endocrinology Branch, Reproductive Toxicology Division, NHEERL, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC 27711, USA. stoker.tammy@epa.gov
Ferrell
J M
JM
Laws
S C
SC
Cooper
R L
RL
Buckalew
A
A
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000145:classification / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010413:Penis / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D010472:Perchlorates / Q000145:classification / Q000633:toxicity*; D000644:Quaternary Ammonium Compounds / Q000145:classification / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012741:Sexual Maturation / Q000187:drug effects*; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology; D013963:Thyroid Hormones / Q000097:blood; D018675:Toxicity Tests / Q000379:methods; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D014881:Water Supply
D052244:Endocrine Disruptors; D010472:Perchlorates; D000644:Quaternary Ammonium Compounds; D013963:Thyroid Hormones; D014874:Water Pollutants, Chemical; C053506:ammonium perchlorate