title: Hepatic genotoxicity and toxicogenomic responses in Muta™Mouse males treated with dibenz[a,h]anthracene.
abstract: Dibenz[a,h]anthracene (DB[a,h]A) is a polycyclic aromatic hydrocarbon that is a by-product of combustion and a potent carcinogen. Few studies have investigated the effects of DB[a,h]A on mRNA and microRNA expression to dissect the mechanisms involved in carcinogenesis. In this study, mature male mice (Muta(™)Mouse) were exposed to 6.25, 12.5 and 25mg/kg/day DB[a,h]A by oral gavage for 28 consecutive days. Results were compared with mice similarly exposed to benzo[a]pyrene (B[a]P) in our previous work. Liver DNA adduct levels and lacZ mutant frequency increased dose dependently for both chemicals. Aryl hydrocarbon receptor (AhR) potency was greater for DB[a,h]A than B[a]P using the chemical-activated luciferase expression assay. Microarray analysis revealed 19 up-regulated and 22 down-regulated genes (false discovery rate-adjusted P ≤ 0.05; fold change ≥ 1.5) following treatment with 6.25 mg/kg/day DB[a,h]A. Thirteen transcripts were up-regulated and 32 down-regulated in the 12.5mg/kg/day group. The 25mg/kg/day dose had major effects on mRNA expression with 135 up-regulated and 104 down-regulated genes. Overall, perturbations were greater for DB[a,h]A than for B[a]P; in vitro chemical-activated luciferase expression supports that this may be driven by the AhR. Many of the DB[a,h]A-affected genes are implicated in cancer and are essential in vital biological functions including circadian rhythm, glucose metabolism, lipid metabolism, immune response, cell cycle and apoptosis. Although a number of functional groups were similarly affected by B[a]P and DB[a,h]A, in general the responses generated by each chemical were quite distinct. Commonalities included a DNA damage response leading to induction of cell cycle arrest and apoptosis in both Tp53-dependent and Tp53-independent manners. MicroRNA expression was identical for both chemicals, with only miR-34a showing a dose-dependent increase in treated mice.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, 50 Colombine Driveway, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Amal I
authors.initials: AI
authors.lastname: Malik
authors.forename: Andrea
authors.initials: A
authors.lastname: Rowan-Carroll
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lemieux
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Long
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs; D046228:Microarray Analysis; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity; D059645:Mutation Rate
chemical_list: D001551:Benz(a)Anthracenes; D018736:DNA Adducts; D035683:MicroRNAs; D009153:Mutagens; D001564:Benzo(a)pyrene; D008156:Luciferases; C026486:1,2,5,6-dibenzanthracene