title: Performance of urinary and gene expression biomarkers in detecting the nephrotoxic effects of melamine and cyanuric acid following diverse scenarios of co-exposure.
abstract: Although standard nephrotoxicity assessments primarily detect impaired renal function, KIM-1, clusterin, NGAL, osteopontin and TIMP-1 were recently identified biomarkers proposed to indicate earlier perturbations in renal integrity. The recent adulteration of infant and pet food with melamine (MEL) and structurally-related compounds revealed that co-ingestion of MEL and cyanuric acid (CYA) could form melamine-cyanurate crystals which obstruct renal tubules and induce acute renal failure. This study concurrently evaluated the ability of multiplexed urinary biomarker immunoassays and biomarker gene expression analysis to detect nephrotoxicity in F344 rats co-administered 60ppm each of MEL and CYA in feed or via gavage for 28days. The biomarkers were also evaluated for the ability to differentiate the effects of the compounds when co-administered using diverse dosing schedules (i.e., consecutive vs. staggered gavage) and dosing matrixes (i.e., feed vs. gavage). Our results illustrate the ability of both methods to detect and differentiate the severity of adverse effects in the staggered and consecutive gavage groups at much lower doses than previously observed in animals co-exposed to the compounds in feed. We also demonstrate that these urinary biomarkers outperform traditional diagnostic methods and represent a powerful, non-invasive indicator of chemical-induced nephrotoxicity prior to the onset of renal dysfunction.
authors.affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, Laurel, MD 20708, USA. omari.bandele@fda.hhs.gov
authors.forename: Omari
authors.initials: O
authors.lastname: Bandele
authors.forename: Luísa
authors.initials: L
authors.lastname: Camacho
authors.forename: Martine
authors.initials: M
authors.lastname: Ferguson
authors.forename: Renate
authors.initials: R
authors.lastname: Reimschuessel
authors.forename: Cynthia
authors.initials: C
authors.lastname: Stine
authors.forename: Thomas
authors.initials: T
authors.lastname: Black
authors.forename: Nicholas
authors.initials: N
authors.lastname: Olejnik
authors.forename: Zachary
authors.initials: Z
authors.lastname: Keltner
authors.forename: Michael
authors.initials: M
authors.lastname: Scott
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Gamboa da Costa
authors.forename: Robert
authors.initials: R
authors.lastname: Sprando
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics; D000821:Animal Feed / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000652:urine*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000652:urine; D051152:Clusterin / Q000652:urine; D055316:Cystatin C / Q000652:urine; D004781:Environmental Exposure / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics; D008297:Male; D053495:Osteopontin / Q000652:urine; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics / Q000652:urine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014227:Triazines / Q000633:toxicity*
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D051152:Clusterin; D055316:Cystatin C; D000071068:Lipocalin-2; D054834:Lipocalins; D053495:Osteopontin; D011518:Proto-Oncogene Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D014227:Triazines; C498500:Clu protein, rat; C525032:Cst3 protein, rat; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat; C506897:Spp1 protein, rat; C576839:TIMP1 protein, rat; C004632:cyanuric acid; C011907:melamine