Transcriptional Profiling of Dibenzo[def,p]chrysene-induced Spleen Atrophy Provides Mechanistic Insights into its Immunotoxicity in MutaMouse.
Dibenzo[def,p]chrysene (DBC) is the most carcinogenic polycyclic aromatic hydrocarbon (PAH) examined to date. We investigated the immunotoxicity of DBC, manifested as spleen atrophy, following acute exposure of adult MutaMouse males by oral gavage. Mice were exposed to 0, 2.0, 6.2, or 20.0 mg DBC /kg-bw per day, for 3 days. Genotoxic endpoints (DBC-DNA adducts and lacZ mutant frequency in spleen and bone marrow, and red blood cell micronucleus frequency) and global gene expression changes were measured. All of the genotoxicity measures increased in a dose-dependent manner in spleen and bone marrow. Gene expression analysis showed that DBC activates p53 signaling pathways related to cellular growth and proliferation, which was evident even at the low dose. Strikingly, the expression profiles of DBC exposed mouse spleens were highly inversely correlated with the expression profiles of the only published toxicogenomics dataset of enlarged mouse spleen. This analysis suggested a central role for Bnip3l, a pro-apoptotic protein involved in negative regulation of erythroid maturation. RT-PCR confirmed expression changes in several genes related to apoptosis, iron metabolism, and aryl hydrocarbon receptor signaling that are regulated in the opposite direction during spleen atrophy versus benzo[a]pyrene-mediated splenomegaly. In addition, benchmark dose modeling of toxicogenomics data yielded toxicity estimates that are very close to traditional toxicity endpoints. This work illustrates the power of toxicogenomics to reveal rich mechanistic information for immunotoxic compounds and its ability to provide information that is quantitatively similar to that derived from standard toxicity methods in health risk assessment.
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Nikolai L
NL
Chepelev
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Alexandra S
AS
Long
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Andrew
A
Williams
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Byron
B
Kuo
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Rémi
R
Gagné
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Dean A
DA
Kennedy
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London SE1 9NH, UK.
David H
DH
Phillips
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, London SE1 9NH, UK.
Volker M
VM
Arlt
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and.
Paul A
PA
White
*Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada and Carole.Yauk@hc-sc.gc.ca.
Carole L
CL
Yauk
D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D019985:Benchmarking; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000032:analysis; D009928:Organ Specificity; D012156:Reticulocytes / Q000187:drug effects / Q000648:ultrastructure; D017423:Sequence Analysis, RNA; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D043922:Toxicogenetics
C508686:BNip3 protein, mouse; D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C041517:dibenzo(a,l)pyrene
benchmark dose modeling; human health risk assessment; mode of action; spleen