title: Polycystic kidney disease induced in F(1) Sprague-Dawley rats fed para-nonylphenol in a soy-free, casein-containing diet.
abstract: para-Nonylphenol (NP; CAS #84852-15-3), an alkylphenol with a 9-carbon olefin side chain, is widely used in the manufacture of nonionic surfactants, lubricant additives, polymer stabilizers, and antioxidants. Due to its wide commercial use and putative endocrine activity in humans and wildlife, the NTP elected to assess its effects on reproduction in multigenerational studies. To avoid known estrogenic activity of phytoestrogens in soy and alfalfa, a soy- and alfalfa-free, casein-containing diet was used in a range-finding study to determine the doses of NP to be tested further. NP was administered to Sprague-Dawley rats in the diet at 0, 5, 25, 200, 500, 1000, or 2000 ppm to F(0) dams beginning on gestation-day 7. The F(1) pups were weaned at postnatal day (PND) 21, and their exposure via diet was continued at the same dose level as their respective dams. Pup weights from birth through weaning were not significantly different from controls in any dose group, but the average weight of both sexes was significantly less compared to controls, beginning with the PND 28 weighing. The F(1) rats were sacrificed on PND 50 (n = 15, 3 pups of each sex from 5 litters for all dose groups). Terminal body weights of males and females in the 2000-ppm dose group were 74% and 85% of controls, respectively. Severe polycystic kidney disease (PKD) was present in 100% of the 2000 ppm-exposed male and female rats. At 1000 ppm, 67% of males and 53% of females had mild to moderate PKD versus none of either sex in the control and lower-dose groups. The no-adverse-effect level (NOAEL) for PKD was determined to be 500 ppm. Previous studies with comparable duration and route of exposure, but using soy-containing diets, reported either no or only mild PKD at 2000 ppm NP. We conclude that the renal toxicity of NP is highly dependent on the diet on which the animals are maintained. The potential interaction of diet and test compounds on nonreproductive as well as reproductive endpoints should be considered when contemplating the use of special diets formulated to minimize exogenous "hormone" content for the study of the effects of putative endocrine disruptive chemicals.
authors.affiliation: Pathology Associates International, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. jlatendresse@nctr.fda.gov
authors.forename: J R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: R R
authors.initials: RR
authors.lastname: Newbold
authors.forename: C C
authors.initials: CC
authors.lastname: Weis
authors.forename: K B
authors.initials: KB
authors.lastname: Delclos
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D002364:Caseins / Q000008:administration & dosage; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007774:Lactation / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D010636:Phenols / Q000008:administration & dosage / Q000633:toxicity*; D007690:Polycystic Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D030262:Soybean Proteins / Q000008:administration & dosage
chemical_list: D002364:Caseins; D010636:Phenols; D030262:Soybean Proteins; C041594:4-nonylphenol