Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment.
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.
Kramer
Jeffrey A
JA
Pfizer Inc, St. Louis, Missouri, USA.
Pettit
Syril D
SD
Amin
Rupesh P
RP
Bertram
Timothy A
TA
Car
Bruce
B
Cunningham
Michael
M
Curtiss
Sandra W
SW
Davis
John W
JW
Kind
Clive
C
Lawton
Michael
M
Naciff
Jorge M
JM
Oreffo
Victor
V
Roman
Richard J
RJ
Sistare
Frank D
FD
Stevens
James
J
Thompson
Karol
K
Vickers
Alison E
AE
Wild
Stacey
S
Afshari
Cynthia A
CA
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
D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D005839:Gentamicins; D011691:Puromycin; D002945:Cisplatin