Mechanisms of hydrazine toxicity in rat liver investigated by proteomics and multivariate data analysis.
A proteomics approach combined with multivariate data analysis was used to examine the hepatotoxic effect of hydrazine in 30 male Sprague Dawley rats, assigned to four treatment groups and two control groups. Liver samples from the individual animals were resolved by two-dimensional differential gel electrophoresis (2-D DIGE) and protein patterns from the 2-D gels were analyzed by principal component analysis (PCA) and partial least squares regression (PLSR). The PCA plot was able to describe the variation in the protein expression related to dose and time, by separation or clustering of different animal groups. PLSR followed by variable selection (Jack-knifing) was used to select proteins that varied significantly in relation to the dose related response of the hydrazine treatment. The 10 up-regulated and 10 down-regulated proteins with highest rank in the PLSR model were identified by mass spectrometry. Hydrazine treatment induced altered expression of proteins related to lipid metabolism, Ca(2+) homeostasis, thyroid hormone pathways and stress response. Several of the identified proteins have not previously been implicated in hydrazine toxicity and may thus be regarded as new potential biomarkers of induced liver toxicity.
Klenø
Tina Guldberg
TG
Applied Trinomics, Novo Nordisk, Måløv, Denmark.
Leonardsen
Lise Rønnedal
LR
Kjeldal
Helle Ørsted
HØ
Laursen
Steen Møller
SM
Jensen
Ole Nørregaard
ON
Baunsgaard
Dorrit
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods*; D006834:Hydrazines / Q000494:pharmacology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D015999:Multivariate Analysis; D010455:Peptides / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D020543:Proteome; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D015854:Up-Regulation
D000970:Antineoplastic Agents; D002273:Carcinogens; D006834:Hydrazines; D010455:Peptides; D011506:Proteins; D020543:Proteome; C029424:hydrazine; D002118:Calcium