Comparison between male and female Sprague-Dawley rats in the response of urinary biomarkers to injury induced by gentamicin.
Differences were examined between male and female Sprague-Dawley rats in the response of 16 urinary biomarkers (measured using several assay platforms) to renal injury produced by gentamicin administered subcutaneously for 10 days at a dosage of 75 mg/kg. Urinary biomarkers expressed as fold difference from contemporaneous controls and renal histopathology were assessed after 3 and 10 doses. On day 4, minimal proximal tubular changes were observed microscopically in all males but no females; on day 11, more extensive and more severe injury was observed to a similar extent in all animals of both sexes. Modest increases (maximum 5-fold) in all urinary biomarkers (except epidermal growth factor [EGF], which was decreased) on day 4 and marked elevations (maximum 271-fold) on day 11 were seen consistently in both sexes. However, the magnitude of the increases differed between the sexes. On day 4, despite the lack of tubular injury, many biomarkers were more elevated in females than males but this rarely led to statistically significant sex differences; only 2 biomarkers (β2-microglobulin and total protein) showed a greater increase in males than females in line with the histopathology. On day 11, there were many more biomarkers that showed a statistically significant difference between the sexes in fold change with treatment; in line with the results on day 4, the majority of biomarkers were more increased in females than males. It remains unresolved if sex differences in the magnitude of biomarker response at injury threshold would lead to any difference in diagnostic interpretation between the sexes. These data highlight the need for publication of more studies using animals of both sexes to fully explore the influence of sex on the diagnostic performance of the novel biomarkers.
Sanofi R&D, Paris, France jean-charles.gautier@sanofi.com.
Jean-Charles
JC
Gautier
Sanofi R&D, Paris, France.
Thierry
T
Gury
Pfizer, Pearl River, New York, USA.
Magali
M
Guffroy
Covance Laboratory SAS, Porcheville, France.
Régis
R
Masson
Sanofi R&D, Bridgewater, New Jersey, USA.
Richard
R
Khan-Malek
Sanofi R&D, Bridgewater, New Jersey, USA.
David
D
Hoffman
ILSI Health and Environmental Sciences Institute, Washington, D.C., USA.
Syril
S
Pettit
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Ernie
E
Harpur
D000818:Animals; D015415:Biomarkers / Q000652:urine*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D001613:beta 2-Microglobulin / Q000652:urine
D015415:Biomarkers; D005839:Gentamicins; D001613:beta 2-Microglobulin
Sprague-Dawley rats.; assay platforms; gentamicin nephrotoxicity; kidney; sex differences; urinary biomarkers