Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to Di(n-butyl) phthalate during late gestation.

Di(n-butyl) phthalate (DBP) is a commercially important plasticizer and ubiquitous environmental contaminant. Since previous, limited dose-response studies with DBP that reported alterations in male reproductive development and function failed to establish a NOAEL (no-observed-adverse-effect level), an extensive dose-response study was conducted. Pregnant CD rats were given DBP by gavage at 0, 0.5, 5, 50, or 100 mg/kg/day (n = 19-20) or 500 mg/kg/day (n = 11) from gestation day 12 to 21. In male offspring, anogenital distance was decreased at 500 mg DBP/kg/day. Retained areolas or nipples were present in 31 and 90% of male pups at 100 and 500 mg/kg/day, respectively. Preputial separation was not delayed by DBP treatment in males with normal external genitalia, but cleft penis (hypospadias) was observed in 5/58 rats (4/11 litters) at 500 mg/kg/day. Absent or partially developed epididymis (23/58 rats in 9/11 litters), vas deferens (16/58 animals in 9/11 litters), seminal vesicles (4/58 rats in 4/11 litters), and ventral prostate (1/58 animals) occurred at 500 mg/kg/day. In 110-day-old F(1) males, the weights of the testis, epididymis, dorsolateral and ventral prostates, seminal vesicles, and levator ani-bulbocavernosus muscle were decreased at 500 mg/kg/day. At 500 mg/kg/day, widespread seminiferous tubule degeneration was seen in 25/58 rats (in 9/11 litters), focal interstitial cell hyperplasia in 14/58 rats (in 5/11 litters), and interstitial cell adenoma in 1/58 rats (in 1/11 litters). For this 10-day prenatal (embryonic and fetal) exposure to DBP, the NOAEL and LOAEL (lowest-observed-adverse-effect level) were 50 and 100 mg/kg/day, respectively. This is currently the lowest NOAEL described for the toxicity of DBP.

[1]  Division on Earth Guide for the Care and Use of Laboratory Animals , 1996 .

[2]  V. Valli,et al.  Subchronic oral toxicity of di-n-octyl phthalate and di(2-Ethylhexyl) phthalate in the rat. , 1997, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[3]  J. Perchellet,et al.  Studies on sex differentiation in mammals. , 1973, Recent progress in hormone research.

[4]  H. Kay Environmental Health Criteria , 1980 .

[5]  K. Butterworth,et al.  Short-term toxicity study of di-(2-ethylhexyl) phthalate in rats. , 1977, Food and cosmetics toxicology.

[6]  Ronald J. Kendall,et al.  Principles and processes for evaluating endocrine disruption in wildlife , 1996 .

[7]  E. Vaughan,et al.  Nipple differentiation in fetal male rats treated with an inhibitor of the enzyme 5 alpha-reductase: definition of a selective role for dihydrotestosterone. , 1986, Endocrinology.

[8]  P. Grasso,et al.  Studies on dibutyl phthalate-induced testicular atrophy in the rat: effect on zinc metabolism. , 1977, Toxicology and applied pharmacology.

[9]  Sharpe,et al.  Male reproductive health and environmental xenoestrogens. , 1996, Environmental health perspectives.

[10]  R B Conolly,et al.  Quantitative evaluation of alternative mechanisms of blood and testes disposition of di(2-ethylhexyl) phthalate and mono(2-ethylhexyl) phthalate in rats. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[11]  P Fenner-Crisp,et al.  Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? , 1998, Regulatory toxicology and pharmacology : RTP.

[12]  J. Haines,et al.  International programme on chemical safety , 1996, The Lancet.

[13]  L. Gray,et al.  Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat , 1999, Toxicology and industrial health.

[14]  T. Orton,et al.  Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man. , 1986, Environmental health perspectives.

[15]  G. Boorman,et al.  Focal Interstitial Cell Hyperplasia, Testes, Rat , 1987 .

[16]  L. Gray,et al.  The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro , 1999, Toxicology and industrial health.

[17]  L. A. Dostal,et al.  Testicular toxicity and reduced Sertoli cell numbers in neonatal rats by di(2-ethylhexyl)phthalate and the recovery of fertility as adults. , 1988, Toxicology and applied pharmacology.

[18]  K. Catt,et al.  Ontogeny of gonadotropin receptors in the fetal and neonatal rat testis. , 1984, Endocrinology.

[19]  P. Foster,et al.  Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. , 1999, Toxicology and applied pharmacology.

[20]  F. Neumann,et al.  Aspects of androgen-dependent events as studied by antiandrogens. , 1970, Recent progress in hormone research.

[21]  M. Sar,et al.  Impaired male sexual development in perinatal Sprague-Dawley and Long-Evans hooded rats exposed in utero and lactationally to p,p'-DDE. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[22]  I. Huhtaniemi,et al.  Preputial separation as an external sign of pubertal development in the male rat. , 1977, Biology of reproduction.

[23]  L. Gray,et al.  Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p′-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproduc , 1999, Toxicology and industrial health.

[24]  P. Foster,et al.  Study of the testicular effects and changes in zinc excretion produced by some n-alkyl phthalates in the rat. , 1980, Toxicology and applied pharmacology.

[25]  P. Foster,et al.  Male reproductive tract malformations in rats following gestational and lactational exposure to Di(n-butyl) phthalate: an antiandrogenic mechanism? , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  A. Saillenfait,et al.  Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of Di-n-butyl Phthalate Administered to Pregnant Rats , 1998 .

[27]  G. Trimarchi,et al.  Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat. , 1998, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[28]  P. Foster,et al.  Changes in ultrastructure and cytochemical localization of zinc in rat testis following the administration of di-n-pentyl phthalate. , 1982, Toxicology and applied pharmacology.

[29]  T. Gray,et al.  Effect of some phthalate esters and other testicular toxins on primary cultures of testicular cells. , 1984, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[30]  M. Ema,et al.  Teratogenic evaluation of di-n-butyl phthalate in rats. , 1993, Toxicology letters.