title: Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment.
abstract: Microarrays allow for the simultaneous measurement of changes in the levels of thousands of messenger RNAs within a single experiment. As such, the potential for the application of transcription profiling to preclinical safety assessment and mechanism-based risk assessment is profound. However, several practical and technical challenges remain. Among these are nomenclature issues, platform-specific data formats, and the lack of uniform analysis methods and tools. Experiments were designed to address biological, technical, and methodological variability, to evaluate different approaches to data analysis, and to understand the application of the technology to other profiling methodologies and to mechanism-based risk assessment. These goals were addressed using experimental information derived from analysis of the biological response to three mechanistically distinct nephrotoxins: cisplatin, gentamicin, and puromycin aminonucleoside. In spite of the technical challenges, the transcription profiling data yielded mechanistically and topographically valuable information. The analyses detailed in the articles from the Nephrotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute suggest at least equal sensitivity of microarray technology compared to traditional end points. Additionally, microarray analysis of these prototypical nephrotoxicants provided an opportunity for the development of candidate bridging biomarkers of nephrotoxicity. The potential future extension of these applications for risk assessment is also discussed.
authors.affiliation: Pfizer Inc, St. Louis, Missouri, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kramer
authors.forename: Syril D
authors.initials: SD
authors.lastname: Pettit
authors.forename: Rupesh P
authors.initials: RP
authors.lastname: Amin
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Bertram
authors.forename: Bruce
authors.initials: B
authors.lastname: Car
authors.forename: Michael
authors.initials: M
authors.lastname: Cunningham
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Curtiss
authors.forename: John W
authors.initials: JW
authors.lastname: Davis
authors.forename: Clive
authors.initials: C
authors.lastname: Kind
authors.forename: Michael
authors.initials: M
authors.lastname: Lawton
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Naciff
authors.forename: Victor
authors.initials: V
authors.lastname: Oreffo
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.forename: James
authors.initials: J
authors.lastname: Stevens
authors.forename: Karol
authors.initials: K
authors.lastname: Thompson
authors.forename: Alison E
authors.initials: AE
authors.lastname: Vickers
authors.forename: Stacey
authors.initials: S
authors.lastname: Wild
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Afshari
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005839:Gentamicins / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011691:Puromycin / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D018570:Risk Assessment
chemical_list: D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D005839:Gentamicins; D011691:Puromycin; D002945:Cisplatin