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Developmental toxicity of DEHP



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*Developmental toxicity of DEHP:

Animal

Route of exposure

Dose

Time

Toxicity result

Reference

Rats

Oral

750 mg/kg

From gestational day 14 to postnatal day 3

* Male pups from the DEHP-treated group displayed shortened AGDs and reduced testis weights.

* As infants, males in the DEHP-treated group displayed female-like areolas/nipples and a significant incidence of reproductive malformations.

* DEHP altered sexual differentiation in rats

(1)

Rats(SD)

Oral

250, 500 or 1000 mg/kg

From gestation days 7–18

* Multiple abnormalities in male germ cells in fetal testis.

* In the 250- and 500-mg/kg groups, adverse effects on male testis development were observed

(2)

Rats (SD)

Oral

0, 375, 750 or 1500 mg/kg

From gestation day 3 to postnatal day 21

* Dose-related adverse effects in male sex organ development and sperm quality were found, as well as low sexual activity.

(3)

Rats (SD)

Oral and I.V.

0, 60, 300 or 600 mg/kg bw per day for 21 days

90 day

* A dose-dependent increase in the severity of testicular lesions was observed and the effect was modestly stronger in rats exposed orally.

* No effects on sperm count, sperm morphology or sperm motility were observed.

(4)

Rat (F344)(Man and Female)

Oral

0, 100, 500, 2500 or 12500 ppm

104 weeks

* DEHP decrease in mean relative testes weight with the highest dose.

* Bilateral aspermatogenesis was observed.

* No effect on mean relative uterine weight was observed in this study.

(5)

Rats(Wistar)(Female)

Oral

0.015, 0.045, 0.135, 0.405 ,1.215, 5, 15, 45, 135 and 405 mg /kg /day

From gestation day 6 to lactation day 21

* Nipple retention and reduced AGD were observed in male offspring.

* Delayed preputial separation was observed in animals exposed to higher doses.

(6)

Mouse (B6C3F)(Man and Female)

Oral

0, 100, 500, 1500 or 6000 ppm

104 weeks

* Immature/abnormal epididymal sperm and bilateral hypospermia of the testes were observed in male mice.

* A significant reduction in mean relative uterus weight was observed in female mice at the highest dose.

(7)

Mouse (wild-type and Pparα-null Sv/129)(PPAR alpha-null)

Oral

12000 ppm

13 weeks

* Spermatogenesis was also diminished and giant cells were found within the epididymis by 8–16 weeks.

* DEHP can also act through PPAR alpha-independent pathways in mediating renal and testicular toxicity.

(8)

Marmosets(male)

Oral

0, 100, 500 or 2500 mg/kg/day

13 weeks

* No significant changes were observed in testis weights or histopathology of the testis, epididymis, seminal vesicles or prostate.

(9)

Marmosets(male and female)

Oral

0, 100, 500 or 2500 mg/kg

65 weeks

* No microscopic changes were found in male gonads or secondary sex organs.

* In females, increased ovarian and uterine weights and elevated blood E2 levels were observed.

* The activity of several liver enzymes involved in the biosynthesis of sex hormones (CYP contents, testosterone, 6β-hydroxylase and lauric acid ω-1-hydroxylase) was increased.

(10)

參考資料

  1. Gray LE, Jr., Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci. 2000;58:350-65.
  2. Shirota M, Saito Y, Imai K, Horiuchi S, Yoshimura S, Sato M, et al. Influence of di-(2-ethylhexyl)phthalate on fetal testicular development by oral administration to pregnant rats. J Toxicol Sci. 2005;30:175-94.
  3. Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. Environ Health Perspect. 2001;109:229-37.
  4. Cammack JN, White RD, Gordon D, Gass J, Hecker L, Conine D, et al. Evaluation of reproductive development following intravenous and oral exposure to DEHP in male neonatal rats. Int J Toxicol. 2003;22:159-74.
  5. David RM, Moore MR, Finney DC, Guest D. Chronic toxicity of di(2-ethylhexyl)phthalate in rats. Toxicol Sci. 2000;55:433-43.
  6. Andrade AJ, Grande SW, Talsness CE, Grote K, Golombiewski A, Sterner-Kock A, et al. A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): effects on androgenic status, developmental landmarks and testicular histology in male offspring rats. Toxicology. 2006;225:64-74.
  7. David RM, Moore MR, Finney DC, Guest D. Chronic toxicity of di(2-ethylhexyl)phthalate in mice. Toxicol Sci. 2000;58:377-85.
  8. Ward JM, Peters JM, Perella CM, Gonzalez FJ. Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha-null mice. Toxicol Pathol. 1998;26:240-6.
  9. Kurata Y, Kidachi F, Yokoyama M, Toyota N, Tsuchitani M, Katoh M. Subchronic toxicity of Di(2-ethylhexyl)phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. Toxicol Sci. 1998;42:49-56.
  10. Tomonari Y, Kurata Y, David RM, Gans G, Kawasuso T, Katoh M. Effect of di(2-ethylhexyl) phthalate (DEHP) on genital organs from juvenile common marmosets: I. Morphological and biochemical investigation in 65-week toxicity study. J Toxicol Environ Health A. 2006;69:1651-72.

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