Induction of hepatic cytochromes P450 in dogs exposed to a chronic low dose of polychlorinated biphenyls.
Induction of cytochrome P450 isoforms, specifically CYP1A1, and their catalytic activities are potential biomarkers of environmental contamination by polychlorinated biphenyls (PCBs). In this study, dogs were exposed to 25 ppm or 5 ppm Aroclor 1248 (PCB mixture) daily in their diet for 10 or 20 weeks, respectively. Relative to controls, hepatic microsomes from dogs dosed with PCBs had higher levels of CYP1A1 detected in immunoblots and higher levels of EROD activity, but low levels of induction for CYP2B and PROD activity. Concentrations of 96 PCB congeners in serum and liver were evaluated using capillary chromatography. Results showed that all dogs exposed to PCB mixtures had higher levels of PCB in serum and liver. Dogs preferentially sequestered highly chlorinated PCB congeners in liver relative to serum. With these experiments, we demonstrated that EROD activity was a potentially sensitive marker of PCB exposure at 5 and 25 ppm. Furthermore, CYP1A1 and EROD activity were maximally induced in dogs consuming dietary concentrations only 2.5 times the maximal permissible level for human food (FDA). The value of CYP1A1 induction as a biomarker of PCB exposure was tenuous because neither CYP1A1 levels nor EROD activity correlated with total PCB body burden. However, a small subset of congeners were identified in liver that may strongly influence EROD and PROD induction. Finally, two dogs in the 25 ppm dose group were fasted for 48 h. After 24 h of fasting, several new congeners appeared in the serum and remained in the serum for the remainder of the fast. The fast caused a 293% increase in PCB concentration in serum. This increase has strong implications regarding mobilization of toxic PCBs in wildlife during fasting (e.g., migration, hibernation).
Field of Environmental Toxicology, Center for the Environment, Cornell University, Ithaca, NY 14853, USA.
P J
PJ
Korytko
A C
AC
Casey
B
B
Bush
F W
FW
Quimby
D000818:Animals; D001140:Aroclors / Q000097:blood / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D019363:Cytochrome P-450 CYP1A1 / Q000032:analysis / Q000097:blood / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000032:analysis / Q000097:blood / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000097:blood / Q000633:toxicity*; D005215:Fasting; D005260:Female; D015151:Immunoblotting; D008099:Liver / Q000737:chemistry; D008297:Male; D013250:Steroid Hydroxylases / Q000378:metabolism; D013997:Time Factors
D001140:Aroclors; D015415:Biomarkers; D004785:Environmental Pollutants; C028617:aroclor 1248; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase