Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid

Cynthia B Stine; Renate Reimschuessel; Zachary Keltner; Cristina B Nochetto; Thomas Black; Nicholas Olejnik; Michael Scott; Omari Bandele; Sarah M Nemser; Andriy Tkachenko; Eric R Evans; Tina C Crosby; Olgica Ceric; Martine Ferguson; Betsy J Yakes; Robert Sprando

doi:10.1016/j.fct.2014.02.029

Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid

Food Chem Toxicol. 2014 Jun:68:142-53. doi: 10.1016/j.fct.2014.02.029. Epub 2014 Feb 28.

Authors

Cynthia B Stine¹, Renate Reimschuessel², Zachary Keltner³, Cristina B Nochetto⁴, Thomas Black⁵, Nicholas Olejnik⁶, Michael Scott⁷, Omari Bandele⁸, Sarah M Nemser⁹, Andriy Tkachenko¹⁰, Eric R Evans¹¹, Tina C Crosby¹², Olgica Ceric¹³, Martine Ferguson¹⁴, Betsy J Yakes¹⁵, Robert Sprando¹⁶

Affiliations

¹ Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: cynthia.stine@fda.hhs.gov.
² Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: renate.reimschuessel@fda.hhs.gov.
³ 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.
⁴ Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: cristina.nochetto@fda.hhs.gov.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: sarah.nemser@fda.hhs.gov.
¹⁰ Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: andriy.tkachenko@fda.hhs.gov.
¹¹ Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: eric.evans@fda.hhs.gov.
¹² Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: tina.crosby@fda.hhs.gov.
¹³ Center for Veterinary Medicine, US Food and Drug Administration, 8401 Muirkirk Rd, Laurel, MD 20708, USA. Electronic address: olgica.ceric@fda.hhs.gov.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.

PMID: 24582682
DOI: 10.1016/j.fct.2014.02.029

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.

Keywords: Cyanuric acid; Melamine; Rats; Reproductive toxicity.

Published by Elsevier Ltd.

MeSH terms

Administration, Oral
Animal Feed
Animals
Blood Urea Nitrogen
Body Weight / drug effects
Creatinine / blood
Dose-Response Relationship, Drug
Female
Food Contamination / analysis
Male
Maternal Exposure*
Organ Size / drug effects
Rats
Renal Insufficiency / chemically induced
Renal Insufficiency / pathology*
Reproduction / drug effects*
Toxicity Tests
Triazines / administration & dosage
Triazines / blood
Triazines / toxicity*

Substances

Triazines
Creatinine
cyanuric acid
melamine