Short-term toxicity study of di-(2-ethylhexyl) phthalate in rats

Gray, Tim J.B.; Butterworth, K.R.; Gaunt, I.F.; Grasso, P.; Gangolli, S.D.

doi:10.1016/s0015-6264(77)80003-5

Cited by 127 publications

(33 citation statements)

References 35 publications

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“…Consistent with a previous report (16), reduced body weight gain upon exposure to DEHP was indicative of toxicity and not completely attributed to food consumption, as the latter was largely unaffected. The observations of DEHP-induced gonadotoxicity were also in agreement with the previous studies (5-7), though relatively milder since adult rats are less susceptible to (34), since high levels of zinc are essential for the maturation of sperm and maintenance of germinal epithelium (9).…”

Section: Discussionsupporting

confidence: 90%

“…The objectives of this investigation were to assess the sensitivity of sexually mature rats to the toxic responses induced by the dietary administration of DEHP, to examine the reproductive performance of male rats following exposure to the gonadotoxic and subgonadotoxic dose levels, and to observe the patterns of recovery from toxicity upon the discontinuance of exposure to DEHP Dietary administration of DEHP in the present study produced phthalate ester characteristic toxicity in rats as indicated by reduced body weight gain, reduced testicular and accessory sex-organ weights, loss oftesticular zinc, induction of seminiferous tubular atrophy, lowered serum triglycerides and cholesterol, and hepatomegaly (5)(6)(7)16,17). The toxic response to DEHP was dose-dependent and statistically significant with varying severities depending upon the target tissue.…”

Section: Discussionmentioning

confidence: 91%

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Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Agarwal¹,

Eustis²,

Lamb³

et al. 1986

Environ Health Perspect

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Dietary exposure of adult male F344 rats to 0, 320, 1250, 5000, or 20,000 ppm DEHP for 60 consecutive days resulted in a dose-dependent reduction in total body, testis, epididymis, and prostate weights at 5000 and 20,000 ppm. Degenerative changes were observed in testis, along with decreased testicular zinc content, reduced epididymal sperm density and motility, and increased occurrence of abnormal sperm at 20,000 ppm. There was a trend towards reduced testosterone and increased luteinizing hormone and follicle stimulating hormone in serum at 5000 and 20,000 ppm. The mean percentage of fertile animals was unchanged and reduction in fertility parameters, although not marked in severity, were correlated with gonadal effects. Average litter size was reduced at 20,000 ppm, but initial pup weights and growth were unaffected. There were no grossly observed abnormalities in the offspring and the rate of neonatal deaths was similar in control and DEHP treated groups. Characteristic toxicity manifestations of DEHP included dose-dependent enlargement of liver and reduced sperm triglycerides and cholesterol. Additionally, serum albumin and total proteins were dose dependently increased upon treatment with DEHP. Cessation of exposure to DEHP initiated partial to complete recovery from toxicity in most cases. The magnitude of recovery were variable with that ofthe gonads being slower than other systems. These data suggest a lack of reproductive dysfunction in F344 male rats at DEHP doses below 20,000 ppm which produced measurable testicular degeneration and afflicted epididymal sperm morphology under the present experimental conditions.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 91%

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Agarwal¹,

Eustis²,

Lamb³

et al. 1986

Environ Health Perspect

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“…The testicular toxicity of di(2-ethylhexyl) phthalate (DEHP) has been recognized for many years (1)(2)(3). In rats, repeated administration of DEHP results in seminiferous tubular atrophy characterized by a loss of the meiotic and post-meiotic germ cell populations from the seminiferous epithelium (4).…”

Section: Introductionmentioning

confidence: 99%

Aspects of the testicular toxicity of phthalate esters.

Gray¹,

Gangolli²

1986

Environ Health Perspect

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Di(2-ethylhexyl) phthalate (DEHP) produced seminiferous tubular atrophy and reductions in seminal vesicle and prostate weight in 4-week-old, but not in 15-week-old rats. Di-n-pentyl phthalate (DPP) did produce atrophy in the older rats but this developed more slowly than in young animals. Coadministration of testosterone or gonadotrophins did not protect against phthalate-induced testicular toxicity but did partly reverse the depression of seminal vesicle and prostate weight. Secretion of seminiferous tubule fluid and androgen binding protein by the Sertoli cells was markedly suppressed within 1 hr of a dose of DPP or mono-2-ethylhexyl phthalate (MEHP) in immature rats. This occurred less rapidly in mature rats.[14C]Mono-npentyl phthalate and [14C]MEHP penetrated the blood testis barrier only to a very limited extent. These findings and the early morphological changes in the Sertoli cells produced by DPP suggest that phthalate esters may act initially to cause Sertoli cell injury, the subsequent loss of germ cells occurring as a consequence of this.Some features of the testicular lesion could be reproduced in primary cocultures of rat Sertoli and germ cells. Structure activity studies with a range of phthalate monoesters showed good agreement between the induction of germ cell detachment in culture and testicular toxicity in vivo. Three metabolites of MEHP (metabolites V, VI, and IX) were much less toxic in culture than MEHP itself, suggesting that the latter may be the active testicular toxin from DEHP.

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“…The toxic effect on the testis was similarly observed with a variety of phthalate esters such as di-(2-ethylhexyl) phthalate (DEHP) (Gray et al, 1977), dibutylphthalate, (Cater et al, 1977) and di-n-pentyl phthalate (Creasy et al, 1987). Among a variety of phthalate esters, DEHP has been investigated most frequently as a representative substance of phthalic acid esters.…”

Section: Introductionmentioning

confidence: 98%

Subcellular Distribution of Di-(2-Ethylhexyl)phthalate in Rat Testis

et al. 2004

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-Subcellular distribution of di-(2-ethylhexyl)phthalate (DEHP) in the testis was studied by single oral administration of [3,4,5, H]-phthalic acid di-(2-ethylhexyl) ester (DEHP-3 H) or phthalic acid di-(2-ethyl[1-3 H]hexyl) ester ( 3 H-DEHP) to 8-week-old male rats. Autoradiographs and electron microscopic autoradiographs were prepared from the testis, liver and kidney at 6 and 24 hr after administration and distribution of radioactive materials in the tissues were observed. In the autoradiographic specimen at 6 hr after administration of DEHP 3 H-labeled at phthalic acid moiety (DEHP-3 H), many grains were observed in the testis, mainly at the basal area of seminiferous tubules at the stages IX to I of the spermatogenic cycle. Electron microscopic autoradiographs taken at the same time revealed that localization of grains were in the smooth-surfaced endoplasmic reticulum and mitochondria of Sertoli cells. A few grains were also present at the Golgi apparatus and lysosome of Sertoli cells, and at the interfaces between the Sertoli cells or between Sertoli cells and spermatocytes, and in the cytoplasm of spermatocytes. Autoradiographs of the liver revealed grains in the centrilobular hepatocytes, localized at mitochondria, roughsurfaced endoplasmic reticulum and peroxisomes. In the kidney, the radioactivity was localized at the brush border of the tubular cells in the pars recta of proximal tubules. In the 24-hr specimen, the grain density in the seminiferous tubules obviously decreased. On the other hand, by autoradiography with DEHP 3 H-labeled at the alcohol ( 3 H-DEHP), only a few grains were observed in autoradiographs of the testes at 6 hr after administration. No grains were noted in autoradiographs of the liver and kidney with 3 H-DEHP. The results showed that the phthalic acid ester was splitted rapidly in the body and only the phthalic acid moiety distributed into the cells.

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Short-term toxicity study of di-(2-ethylhexyl) phthalate in rats

Cited by 127 publications

References 35 publications

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Aspects of the testicular toxicity of phthalate esters.

Subcellular Distribution of Di-(2-Ethylhexyl)phthalate in Rat Testis

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