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Transgenerational Effects of Di(2-ethylhexyl) Phthalate in the SD Male Rat
Citation:
GRAY, L. E., N. J. BARLOW, K. HOWDESHELL, J. OSTBY, J. R. FURR, AND C. L. GRAY. Transgenerational Effects of Di(2-ethylhexyl) Phthalate in the SD Male Rat. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 110(2):411-425, (2009).
Impact/Purpose:
The study confirms the NOAEL reported for DEHP in an unpublished NTP report. The NTP data has been used by the EU for a risk assessment on DEHP and our publication will support this assessment and provide the information to the scientific community in peer-reviewed form. In addition, we define male reproductive tract alterations characteristic of the Phthalate Syndrome and propose new methods of data analysis, based upon a syndrome analysis. We also demonstrate the added value in examining more than one pup per litter after weaning, an approach that could ultimately result in reduced animal use since fewer litters are required to detect statistical significance than if only one pup per litter is examined which is now the standard approach (resulted in a waste of animals that are not examined at all).
Description:
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 the current study, SD rat dams were dosed by gavage from gestational day 8 to day 17 of lactation with 0, 11, 33, 100 or 300 mg DEHP/kg/d. On PND 18, some of the male offspring continued to be exposed to DEHP via gavage from weaning through puberty (18 to 63-65 days of age; PUB cohort) (16-20/dose), whereas males in the IUL cohort were not exposed after PND17. The PUB cohort was necropsied at 63-65 days of age and the IUL cohort was necropsied after reaching full maturity. In total, the study examined reproductive organ weights, gross pathology of the reproductive tract and histopathology of testes and epididymides in 71-93 males/group from 12-14 litters/group. Anogenital distance at birth was reduced in males in the 300 mg/kg/d group and they displayed retained areolae/nipples as infants. In the IUL and PUB males, all androgen dependent organ weights were decreased by DEHP treatment. Glans penis, ventral prostate, seminal vesicle, levator ani-bulbocavernosus, Cowper’s gland, testis and epididymal weights were significantly reduced at 300 mg/kg/d. In the PUB cohort, preputial separation was delayed (1.6 and 3.5 days at 100 and 300 mg/kg/d, respectively), liver weight (11 mg/kg/d and higher) and adrenal weights (100 mg/kg/d) and epididymal sperm counts were reduced. In addition, in the IUL cohort, seminal vesicle was reduced at 100 mg/kg/d and testis weight was reduced at 300 mg/kg/d. In contrast, serum testosterone and estradiol levels were unaffected in either the PUB or IUL cohorts. The DEHP dose-response seen in the current study is remarkably similar to that reported from a National Toxicology Program multigenerational study (Foster, 2006) which reported NOAEL-LOAELs of 5 and 10 mg DEHP/kg/d respectively via the diet.
