Comparative responsiveness of hypothyroxinemia and hepatic enzyme induction in Long-Evans rats versus C57BL/6J mice exposed to TCDD-like and phenobarbital-like polychlorinated biphenyl congeners.
Numerous mechanisms have been postulated to explain how polyhalogenated aromatic hydrocarbons alter thyroid homeostasis with almost all data derived from studies using the rat. This study compared the sensitivity of rats and mice to polychlorinated biphenyl (PCB)-induced hypothyroxemia. Male and female C57BL/6J mice and Long-Evans rats were dosed orally for 4 consecutive days with either PCB126 (0.03-300.0 microg/kg/day) or PCB153 (0.3-300.0 mg/kg/day). Trunk blood and livers were collected 24 h after the last dose and used to determine total serum thyroxine (T(4)) and hepatic microsomal T(4) glucuronidation activity. Hepatic microsomal ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-deethylase (PROD) activities were also determined as markers for Ah receptor or phenobarbital response unit activation, respectively. PCB126 did not affect T(4) in the mouse but decreased T(4) (up to 50%) in the rat. PCB153 decreased T(4) (up to 80%) in both the rat and the mouse. PCB126 increased EROD in both rats (12- to 22-fold) and mice (15- to 20-fold). PCB153 induced hepatic PROD activity in both rats (30-fold) and mice (4-fold). T(4) glucuronidation was increased approximately 2- to 3-fold in both rats and mice treated with PCB153. PCB126 increased T(4) glucuronidation 13-fold in rats but only marginally (20%) in mice at the highest doses. Western blot analysis confirmed the PCB126-induced changes in expression of UGT1A in rats and the minimal increase in mice. These data suggest that species differences in response to chemicals that induce hypothyroxinemia are due to differential induction of hepatic UGT enzymes.
Craft
Elena S
ES
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, USA.
DeVito
Michael J
MJ
Crofton
Kevin M
KM
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D013045:Species Specificity; D013974:Thyroxine / Q000097:blood / Q000172:deficiency*
D004965:Estrogen Antagonists; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D014453:Glucuronosyltransferase; D013974:Thyroxine; C023035:3,4,5,3',4'-pentachlorobiphenyl; C014024:2,4,5,2',4',5'-hexachlorobiphenyl