title: Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat.
abstract: Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration-response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC50 values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for inhibition was similar for the other test chemicals, with: PTU>MBT>DPM>4POP>PERC for rat TPO and MBT>PTU>DPM>4POP>PERC for porcine TPO. These data support the extrapolation of porcine TPO data to potential thyroid-disrupting activity in rodent models to evaluate TPO-inhibiting chemicals.
authors: Oak Ridge Institute for Science and Education, Oak Ridge, TN, United States; Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
authors: Katie B
authors: KB
authors: Paul
authors: Joan M
authors: JM
authors: Hedge
authors: Chitralekha
authors: C
authors: Macherla
authors: Dayne L
authors: DL
authors: Filer
authors: Emily
authors: E
authors: Burgess
authors: Steven O
authors: SO
authors: Simmons
authors: Kevin M
authors: KM
authors: Crofton
authors: Michael W
authors: MW
authors: Hornung
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006139:Guaiacol / Q000378:metabolism; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors*; D008297:Male; D008861:Microsomes / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D013045:Species Specificity; D013552:Swine; D013961:Thyroid Gland / Q000187:drug effects*; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D015262:Xenobiotics; D006139:Guaiacol; D007453:Iodide Peroxidase
keywords: 2-mercaptobenzothiazole; 3,5-dimethylpyrazole-1-methanol; 4-n-nonylphenol; 4-propoxyphenol; 4POP; 50% inhibitory concentration; 6-propylthiouracil; CCP; DBP; DEHP; DEP; DIT; DPM; EGF; IC(50); IOA; Interspecies comparison; LCB; MBT; MIT; MMI; MPO; NIS; PERC; PNP; PTU; T3; T4; TCS; TPO; TSH; Tg; Thyroid disruption; Thyroperoxidase; UCB; complement control protein repeat domain; dibutylphthalate; diethylhexylphthalate; diethylphthalate; diiodotyrosine; epidermal growth factor; hTPO; human thyroperoxidase; iopanoic acid; lower confidence bound; methimazole; monoiodotyrosine; myeloperoxidase; pTPO; porcine thyroperoxidase; rTPO; rat TPO; sodium perchlorate; sodium-iodide symporter; thyroglobulin; thyroid-stimulating hormone; thyroperoxidase; thyroxine; triclosan; triiodothyronine; unb; unbounded; upper confidence bound