title: Impact of pregnancy on the pharmacokinetics of dibenzo[def,p]chrysene in mice.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated during combustion. Dibenzo[def,p]chrysene (DBC) is a high molecular weight PAH classified as a 2B carcinogen by the International Agency for Research on Cancer. DBC crosses the placenta in exposed mice, causing carcinogenicity in offspring. We present pharmacokinetic data of DBC in pregnant and nonpregnant mice. Pregnant (gestational day 17) and nonpregnant female B6129SF1/J mice were exposed to 15mg/kg DBC by oral gavage. Subgroups of mice were sacrificed up to 48h postdosing, and blood, excreta, and tissues were analyzed for DBC and its major diol and tetrol metabolites. Elevated maximum concentrations and areas under the curve of DBC and its metabolites were observed in blood and tissues of pregnant animals compared with naïve mice. Using a physiologically based pharmacokinetic (PBPK) model, we found observed differences in pharmacokinetics could not be attributed solely to changes in tissue volumes and blood flows that occur during pregnancy. Measurement of enzyme activity in naïve and pregnant mice by activity-based protein profiling indicated a 2- to 10-fold reduction in activities of many of the enzymes relevant to PAH metabolism. Incorporating this reduction into the PBPK model improved model predictions. Concentrations of DBC in fetuses were one to two orders of magnitude below maternal blood concentrations, whereas metabolite concentrations closely resembled those observed in maternal blood.
authors.affiliation: Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, USA. susan.crowell@pnnl.gov
authors.forename: Susan Ritger
authors.initials: SR
authors.lastname: Crowell
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Jolen J
authors.initials: JJ
authors.lastname: Soelberg
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Sadler
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Wright
authors.forename: William M
authors.initials: WM
authors.lastname: Baird
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Richard A
authors.initials: RA
authors.lastname: Corley
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D001580:Benzopyrenes / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics*; D065633:Cytochrome P-450 CYP1B1; D005260:Female; D008297:Male; D051379:Mice; D008954:Models, Biological; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; C041517:dibenzo(a,l)pyrene
keywords: PBPK modeling; dibenzo[def; gestation.; p]chrysene; polycyclic aromatic hydrocarbons; pregnancy