Diversity Outbred Mice Identify Population-Based Exposure Thresholds and Genetic Factors that Influence Benzene-Induced Genotoxicity.
BACKGROUND
Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers.


OBJECTIVE
We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity.


METHODS
We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis.


RESULTS
We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity.


CONCLUSIONS
The genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity.
Division of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Resources (DHHS), Research Triangle Park, North Carolina, USA.
John E
JE
French
Daniel M
DM
Gatti
Daniel L
DL
Morgan
Grace E
GE
Kissling
Keith R
KR
Shockley
Gabriel A
GA
Knudsen
Kim G
KG
Shepard
Herman C
HC
Price
Deborah
D
King
Kristine L
KL
Witt
Lars C
LC
Pedersen
Steven C
SC
Munger
Karen L
KL
Svenson
Gary A
GA
Churchill
D000818:Animals; D021461:Animals, Outbred Strains; D001554:Benzene / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D008040:Genetic Linkage / Q000187:drug effects; D015386:Hazardous Substances / Q000633:toxicity*; D019570:Inhalation Exposure; D051379:Mice; D015162:Micronucleus Tests; D012156:Reticulocytes / Q000187:drug effects; D018570:Risk Assessment; D015238:Sulfotransferases / Q000235:genetics
D015386:Hazardous Substances; D015238:Sulfotransferases; D001554:Benzene