Polycystic Kidney Disease Induced in F1 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.

Toxic effect of gestational exposure to nonylphenol on F1 male rats

“…Fan et al observed that NP injected orally to pregnant rats induces alteration of reproductive developmental landmarks in their offspring. We observed the effects of NP not reported by Latendresse et al (2001). This is the first study reporting that exposure to NP at the high dose during embryo organogenesis period, from pregnancy day 14 to 19, results in reductions in reproductive landmarks in pups.…”

Renal Tubular Cyst Formation in Newborn Rats Treated with p-Cumylphenol

“…As mentioned before, PKD has been induced by diphenylamine 6 , nordihydroguaiaretic acid 7 , diphenylthiazole 8 , alloxan 9 , streptozocin 9 , ferric-nitrilotriacetate 9 and 2-amino-4,5-diphenylthiazole 10 in young and adult animals and para-nonylphenol 11 and tetrabromobisphenol A 12 in newborn animals. The histological changes induced in newborn rats by para-nonylphenol are characterized by numerous large cystic tubules, which develop mainly in the outer medulla and occasionally contain necrotic epithelial cells and neutrophils, and by patchy areas of chronic interstitial nephritis.…”

“…Similar counterparts are known in other animal species, such as mice, rats, rabbits, springboks, dogs and swine 4,5 . Many investigators have reported that PKDs can be induced by various chemicals, including diphenylamine 6 , nordihydroguaiaretic acid 7 , diphenylthiazole 8 , alloxan 9 , streptozotocin 9 , ferric-nitrilotriacetate 9 and 2-amino-4, 5-diphenylthiazole 10 in young and adult animals and para-nonylphenol 11 and tetrabromobisphenol A 12 in newborn animals. However, the mechanisms responsible for the formation of renal cysts by these compounds are not yet clearly understood, although it has been said that formation of renal cysts may be associated with cell proliferation, alteration of tubular basement membrane and Na/K ATPase localization and/or activity in the target site of the tubules.…”

Myelotoxicity in genistein-, nonylphenol-, methoxychlor-, vinclozolin- or ethinyl estradiol-exposed F1 generations of Sprague–Dawley rats following developmental and adult exposures

“…To determine if endocrine active compounds as mentioned above have any myelotoxicity, the effects of these compounds on the function of bone marrow were evaluated. Studies on the behavior and general toxicity were also performed, and most of these effects have been reported Flynn et al, 2001;Latendresse et al, 2001;Guo et al, 2002;Weis et al, 2002;Ferguson et al, 2003;Karrow et al, 2004;White et al, 2004White et al, , 2005. Exposure of F 1 generation Sprague-Dawley rats to these chemicals was achieved through dams gestationally and lactationally, and through feeding from weaning on PND 22 to PND 64.…”