title: Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid.
abstract: The industrial chemical melamine was used in 2007 and 2008 to raise the apparent protein content in pet feed and watered down milk, respectively. Because humans may be exposed to melamine via several different routes into the human diet as well as deliberate contamination, this study was designed to characterize the effect of high dose melamine or cyanuric acid oral exposure on the pregnant animal and developing fetus, including placental transfer. Clear rectangular crystals formed following a single triazine exposure which is a different morphology from the golden spherulites caused by combined exposure or the calculi formed when melamine combines with endogenous uric acid. Crystal nephropathy, regardless of cause, induces renal failure which in turn has reproductive sequelae. Specifically, melamine alone-treated dams had increased numbers of early and late fetal deaths compared to controls or cyanuric acid-treated dams. As melamine was found in the amniotic fluid, this study confirms transfer of melamine from mammalian mother to fetus and our study provides evidence that cyanuric acid also appears in the amniotic fluid if mothers are exposed to high doses.
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: cynthia.stine@fda.hhs.gov.
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Stine
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: renate.reimschuessel@fda.hhs.gov.
authors.forename: Renate
authors.initials: R
authors.lastname: Reimschuessel
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: zachary.keltner@fda.hhs.gov.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Keltner
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: cristina.nochetto@fda.hhs.gov.
authors.forename: Cristina B
authors.initials: CB
authors.lastname: Nochetto
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: thomas.black@fda.hhs.gov.
authors.forename: Thomas
authors.initials: T
authors.lastname: Black
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: nicholas.olejnik@fda.hhs.gov.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Olejnik
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: michael.scott@fda.hhs.gov.
authors.forename: Michael
authors.initials: M
authors.lastname: Scott
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: omari.bandele@fda.hhs.gov.
authors.forename: Omari
authors.initials: O
authors.lastname: Bandele
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: sarah.nemser@fda.hhs.gov.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nemser
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: andriy.tkachenko@fda.hhs.gov.
authors.forename: Andriy
authors.initials: A
authors.lastname: Tkachenko
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: eric.evans@fda.hhs.gov.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Evans
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: tina.crosby@fda.hhs.gov.
authors.forename: Tina C
authors.initials: TC
authors.lastname: Crosby
authors.affiliation: Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: olgica.ceric@fda.hhs.gov.
authors.forename: Olgica
authors.initials: O
authors.lastname: Ceric
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: martine.ferguson@fda.hhs.gov.
authors.forename: Martine
authors.initials: M
authors.lastname: Ferguson
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740, USA. Electronic address: betsy.yakes@fda.hhs.gov.
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Yakes
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: robert.sprando@fda.hhs.gov.
authors.forename: Robert
authors.initials: R
authors.lastname: Sprando
mesh_terms: D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005506:Food Contamination / Q000032:analysis; D008297:Male; D018811:Maternal Exposure; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D051437:Renal Insufficiency / Q000139:chemically induced / Q000473:pathology*; D012098:Reproduction / Q000187:drug effects*; D018675:Toxicity Tests; D014227:Triazines / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*
chemical_list: D014227:Triazines; D003404:Creatinine; C004632:cyanuric acid; C011907:melamine
keywords: Cyanuric acid; Melamine; Rats; Reproductive toxicity