title: Comparison of TCDD and PCB CYP1A induction sensitivities in fresh hepatocytes from human donors, sprague-dawley rats, and rhesus monkeys and HepG2 cells.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals induce cytochrome P450 1A (CYP1A) gene expression and, at sufficient exposures, cause toxicity. Human health risks from such exposures are typically estimated from animal studies. We tested whether animal models predict human sensitivity by characterizing CYP1A gene expression in cultures of fresh hepatocytes from human donors, rats, and rhesus monkeys and HepG2 human hepatoma cells. We exposed the cells to three aryl hydrocarbon receptor (AhR) ligands of current environmental interest and measured 7-ethoxyresorufin-O-deethylase (EROD) activity and concentrations of CYP1A1 and CYP1A2 mRNA. We found that human cells are about 10-1000 times less sensitive to TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and Aroclor 1254 than rat and monkey cells, that relative potencies among these chemicals are different across species, and that gene expression thresholds exist for these chemicals. Newly calculated rat-human interspecies relative potency factors for PCB 126 were more than 100 times lower than the current rodent-derived value. We propose that human-derived values be used to improve the accuracy of estimates of human health risks.
authors.affiliation: General Electric Company, Global Research Center, Niskayuna, New York 12309, USA. silkworth@crd.ge.com
authors.forename: Jay B
authors.initials: JB
authors.lastname: Silkworth
authors.forename: Aruna
authors.initials: A
authors.lastname: Koganti
authors.forename: Kati
authors.initials: K
authors.lastname: Illouz
authors.forename: Antonio
authors.initials: A
authors.lastname: Possolo
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008253:Macaca mulatta; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2