title: Assessment of subclinical, toxicant-induced hepatic gene expression profiles after low-dose, short-term exposures in mice.
abstract: Gene expression profiling that examines critical, toxicologically-relevant gene and signal-response pathways promises to improve risk assessment and safety evaluation of low-dose chemical exposures. As an approach to achieving this goal, mechanistic interpretations based upon gene expression changes that are determinants of adverse toxicological outcomes were applied to the analysis of low-dose gene expression profiles. RNA for expression profiling was obtained from mice given short-term gavage exposures to diminishing doses of four toxicants: 3,3',4,4',5-pentachlorobiphenyl (PCB126), phenobarbital (PB), isoproterenol (IPR), and lead acetate (PbAc). Lowest doses were below the no-observable effects levels established using standard clinical toxicology parameters. Hepatic gene expression profiles were analyzed using a custom, focused oligonucleotide DNA microarray, the HC ToxArray™, containing toxin-responsive and toxicologically-determinant genes. Expression data were compared to changes in conventional clinical chemistry parameters and drug metabolism activities. PCB126 and PB demonstrated a dose-dependent correlation between minimal changes in biochemical markers, hepatic metabolism and induction of gene expression profiles. PbAc exposure gave a small adaptive profile at the highest dose. IPR- and PCB126-induced changes were detected at doses below those required to alter the traditional biochemical endpoints and included genes with causal roles in hepatic toxicity, insulin resistance, atherosclerosis, angiogenesis and hypertension. Likely adverse phenotypic consequences resulting from expression changes lead to assignments of "Lowest Observed Adverse Transcriptional Expression Levels" (LOATEL) for each agent. These results support the suggestion that altered expression profiles of genes contributing to toxicologically-relevant pathways provide useful tools for reducing uncertainty in establishing no-effect levels and for designing longer-term toxicity studies.
authors.affiliation: Mechanistic Studies Division, Safe Environments Programme, Health Canada, Ottawa, Ontario K1A0K9, Canada.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Zheng
authors.forename: Craig
authors.initials: C
authors.lastname: Parfett
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: Al
authors.initials: A
authors.lastname: Yagminas
authors.forename: Gu
authors.initials: G
authors.lastname: Zhou
authors.forename: George R
authors.initials: GR
authors.lastname: Douglas
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019963:Clinical Chemistry Tests; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007545:Isoproterenol / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D046228:Microarray Analysis; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D009942:Organometallic Compounds / Q000633:toxicity; D010634:Phenobarbital / Q000633:toxicity; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: D009942:Organometallic Compounds; D012333:RNA, Messenger; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D007545:Isoproterenol; C008261:lead acetate; C023035:3,4,5,3',4'-pentachlorobiphenyl; D010634:Phenobarbital