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ToxSci Advance Access published online on May 29, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp109
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Published by Oxford University Press 2009.

TRANSGENERATIONAL EFFECTS OF DI (2-ETHYLHEXYL) PHTHALATE IN THE MALE CRL: CD(SD) RAT: ADDED VALUE OF ASSESSING MULTIPLE OFFSPRING PER LITTER

L. Earl Gray, Jr1, Norman J. Barlow2, Kembra L. Howdeshell1, Joseph S. Ostby1, Johnathan R. Furr1 and Clark L. Gray3

1 Endocrinology Branch, RTD, NHEERL, ORD, USEPA, Research Triangle Park, NC 27711, MD 72, 2525 Highway 54, Research Triangle Park, NC, 27711, gray.earl{at}epa.gov 2 sanofi-aventis, Dept of Drug Safety Evaluation, 9 Great Valley Parkway, Malvern, PA 19355, norman.barlow{at}sanofi-aventis.com 3 Carolina Population Center, University of North Carolina at Chapel Hill, CB # 8120, Chapel Hill, NC 27516

Received April 10, 2009; revision received May 16, 2009; accepted May 18, 2009


  Abstract

In the rat, some phthalates alter sexual differentiation at relatively low dosage levels by altering fetal Leydig cell development and hormone synthesis, thereby inducing abnormalities of the testis, gubernacular ligaments, epididymis and other androgen-dependent tissues. In order to define the dose-response relationship between DEHP and the Phthalate Syndrome of reproductive alterations in F1 male rats, SD rat dams were dosed by gavage from gestational day 8 to day 17 of lactation with 0, 11, 33, 100 or 300 mg/kg/d DEHP (71-93 males/dose from 12-14 litters/dose). Some of the male offspring continued to be exposed to DEHP via gavage from 18 days of age to necropsy at 63-65 days of age (PUB cohort; 16-20/dose). Remaining males were not exposed after PND17 (IUL cohort) and were necropsied after reaching full maturity. Anogenital distance, sperm counts and reproductive organ weights were reduced in F1 males in the 300 mg/kg/d group and they displayed retained nipples. In the IUL cohort, seminal vesicle weight also was reduced at 100 mg/kg/d. In contrast, serum testosterone and estradiol levels were unaffected in either the PUB or IUL cohorts at necropsy. A significant percentage of F1 males displayed one or more Phthalate Syndrome lesions at 11 mg/kg/d DEHP and above. We were able to detect effects in the lower dose groups only because we examined all the males in each litter rather than only 1 male/litter. Power calculations demonstrate how using multiple males versus one male/litter enhances the detection of the effects of DEHP. The results at 11 mg/kg/d confirm those reported from a National Toxicology Program multigenerational study (Foster et al. 2006) which reported NOAEL-LOAELs of 5 and 10 mg/kg/d DEHP respectively via the diet.

Key Words: di(2-ethylhexyl) phthalate; sexual differentiation; phthalate syndrome; dose response.


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