TitleImpact of pregnancy on the pharmacokinetics of dibenzo[def,p]chrysene in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsCrowell, SRitger, Sharma, AK, Amin, S, Soelberg, JJ, Sadler, NC, Wright, AT, Baird, WM, Williams, DE, Corley, RA
JournalToxicol Sci
Volume135
Issue1
Pagination48-62
Date Published2013 Sep
ISSN1096-0929
KeywordsAnimals, Aryl Hydrocarbon Hydroxylases, Benzopyrenes, Carcinogens, Cytochrome P-450 CYP1B1, Female, Male, Mice, Models, Biological, Pregnancy, Pregnancy, Animal, Tissue Distribution
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.

DOI10.1093/toxsci/kft124
Alternate JournalToxicol. Sci.
PubMed ID23744095
PubMed Central IDPMC3748759
Grant List8P41GM103493-10 / GM / NIGMS NIH HHS / United States
P41 GM103493 / GM / NIGMS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States