1. Sponsor Organization: Chemical Industry Institute of Toxicology

2. Project Title: Pathogenesis of testicular lesions induced by late gestational exposure to di(n-butyl) phthalate

3. Project Focus:

• Project Primary Focus: Human Health Effects
• Project Secondary Focus:

4. Description:

Previous studies with di(n-butyl) phthalate (DBP) have indicated that a range of anti-androgenic responses can be observed following late gestational exposure (gestation days 12-21) to DBP. These responses have included a range of reproductive tract malformations (particularly of the epididymis) that would suggest that androgen production/ elimination and / or signaling has been perturbed. Since the androgen necessary for normal male reproductive development arises from the fetal testis, it is necessary to fully understand the pathogenesis of any testicular "lesions" that may be produced since they would have drastic consequences on normal development. In particular two initial observations are deserving of more exploration. Firstly, a preliminary study indicated that following a late gestational exposure a number of testicular lesions were observe in the testes of animals on reaching adulthood. These included major effects on seminiferous tubule structures. The dose response relationships indicate d more changes in incidence, rather than severity of the lesion. In addition a small number of animals at the highest dose level (500 mg/kg/d) were found to have a testicular Leydig cell tumor at 3 months of age. Interstitial cell hyperplasia was also present. Leydig cell tumors are normally regarded as a tumor of old age and occur in c. 5% of male Sprague Dawley rats at 2 years. To see Leydig cell tumors at this age is unprecedented and requires confirmation with more animals. In addition a number of theories exist on the mechanism of Leydig cell tumor induction involving both endocrine (increased pituitary LH levels) and paracrine (response to seminiferous tubule damage and changes in the local testicular environment) changes. The time course for the induction of these effects will become of major interest with such a short duration of exposure to the chemical resulting in the effects observed. Studies investigating the immunolocalization of the androgen receptor (AR) have i ndicated that there is a reduction in expression in the epididymis on gestation day 21. AR is an androgen regulated protein and such a reduction does not necessarily imply a direct action of the chemical on the receptor. Further studies are planned to investigate the early changes in fetal testicular morphology and biochemistry and to relate any such changes as the animals age. Thus following exposure to DBP the testes and other male reproductive structures will be examined in utero, at weaning, puberty and adulthood to examine the progression of any observed changes. This study may provide essential information on how the testis develops and responds to testicular injury when challenged during gestation and whether permanent adverse effects may be induced in the adult.

5. References:

1. Author: Mylchreest E etal
   Title: Male reproductive tract malformations in rats following gestational and lactational exposure to di-n-butyl phthalate: an antiandrogenic mechanism ?
   Citation: Tox Sci 43: 47-60
   Year: 1998
   

2. Author:
   Title:
   Citation:
   Year:
   

6. Inventory Category:

• Primary: Measure
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:
  • Hazard Identification

8. Keywords for Experimental System/Species:

• Species:
  • Rodents
• Study Type:
  • In Vivo
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Reproductive
• Hormonal Measures:
  • Hormone Receptors
  • Pituitary Hormones
  • Sex Steroids
• Level Of Study:
  • Histopathology
  • Gene Expression
• Chemistry Metabolism:
• Life Stage:
  • Male
  • Embryo
  • Infant
  • Puberty
  • Adult
• Risk Assessment:

10. Chemical Agents:

• Phthalates

11. Performing Institution:

• Chemical Industry Institute of Toxicology ;

12. Contact:

Institution: Chemical Industry Institute of Toxicology
Division:
Given Name:
Name: Dr Paul Foster
Title:
Form:
E-Mail: foster@ciit.org
Phone: 919-558-1274
Fax:
Street: 6 Davis Drive, PO Box 12137
Zip:
City: Research Triangle Park, NC 27709
State:
Country:

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