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Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat
Paul, K., J. Hedge, C. Macherla, D. Filer, E. Burgess, Steve Simmons, K. Crofton, AND M. Hornung. Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 312:97-107, (2013).
Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone (TH), is a known target for thyroid-disrupting chemicals (TDC). 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, TDCs 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-propoxylphenol (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.
First, this study evaluated the thyroperoxidase inhibition potential of twelve chemicals,including several for which their potential inhibition activity had never been assessed or reported. This study importantly demonstrated that porcine and rat thyroperoxidase exhibit complete qualitative concordance when challenged by xenobiotics that inhibit or do not inhibit thyroperoxidase. Additionally, there was general quantitative concordance across species models. These data support the use of either porcine thyroperoxidase or rat thyroperoxidase data to model potential effects on human thyroperox•dase function.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
GENETIC AND CELLULAR TOXICOLOGY BRANCH