Effects of phthalate esters on lipid metabolism in various tissues, cells and organelles in mammals.

Bell, Frank P.

doi:10.1289/ehp.824541

Cited by 72 publications

(23 citation statements)

References 73 publications

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“…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%

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: 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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“…Diethyl and dibutyl phthalate also modify the action of drug-metabolizing enzymes (22)(23)(24) but not glucose-6-phosphatase activity (24). Dibutyl phthalate, like DEHP, is reported to lower plasma cholesterol and inhibit cholesterogenesis (25,26), while diethyl phthalate, like DEHP, lowers plasma triglyceride but unlike DEHP does not affect hepatic peroxisomes (12).…”

Section: Introductionmentioning

confidence: 99%

Effects of phthalic acid esters on the liver and thyroid.

Hinton¹,

Mitchell²,

Mann³

et al. 1986

Environ Health Perspect

127

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The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P450 isoenzyme(s) catalyzing w oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fall to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid.The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.

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“…Sci. 66(9): 1119-1124, 2004 The exposure of animals to phthalate esters can result in a significant perturbation of normal lipid metabolism in liver, heart, testis, adrenal gland and brain [4]. The plasticizer, di-(2-ethylhexyl) phthalate (DEHP), is a widespread environmental chemical due to its common use in the production of plastic medical devices and food packaging.…”

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confidence: 99%

Alterations of Activities of Cytosolic Phospholipase A2 and Arachidonic Acid-Metabolizing Enzymes in Di-(2-Ethylhexyl)Phthalate-Induced Testicular Atrophy

Kim

Ishizuka

Kazusaka

et al. 2004

The Journal of Veterinary Medical Science

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ABSTRACT. Di-(2-ethylhexyl) phthalate (DEHP), a peroxisome proliferator-activated receptor α (PPARα) ligand, alters the lipid composition of rat testis, yet the mechanism is unclear. In this study, we investigated the effect of DEHP on the synthesis and metabolism of arachidonic acid (AA), a precursor of eicosanoids, in the testis of prepubertal rats. DEHP (100 and 1,000 mg/kg, 5 days) admini stration caused a significant reduction in activity of cytosolic phospholipase A 2 (cPLA 2 ), the rate-limiting enzyme in the AA and eicosanoid synthesis pathways. DEHP increased the expression of 12-lipoxygenase (12-LOX) in rat testis, whereas cyclooxygenase-2 (COX-2) expr ession was not altered. Cytochrome P450 4A1 (CYP4A1), a product of a PPARα-regulated gene, was markedly increased in the testis by DEHP administration. Taken together, DEHP suppresses cPLA 2 activity and induces the AA metabolizing enzymes such as 12-LOX and CYP4A1, resulting in the reduction of AA level. These data suggest that altered AA metabolic cascades may be related to the decrease of testosterone concentration in DEHP-induced testicular atrophy. KEY WORDS: arachidonic acid, cytosolic phospholipase A 2 , di-(2-ethylhexyl) phthalate, 12-lipoxygenase, testis.J. Vet. Med. Sci. 66(9): 1119-1124, 2004 The exposure of animals to phthalate esters can result in a significant perturbation of normal lipid metabolism in liver, heart, testis, adrenal gland and brain [4]. The plasticizer, di-(2-ethylhexyl) phthalate (DEHP), is a widespread environmental chemical due to its common use in the production of plastic medical devices and food packaging. On the exposure to phthalates for the human, certain populations may be exposed to much higher levels. The range of DEHP concentrations in medical devises are 3.1-650 mg/L [49]. Patients undergoing hemodialysis or blood transfusion received as much as 0.5-360 mg or 14-600 mg of DEHP via plastic medical devices, respectively [17,23]. Ingestion of DEHP, a peroxisome proliferator-activated receptor α (PPARα) ligand, by rats resulted in the increase of non-esterified fatty acids and phospholipids and changes in lipid composition in the testis [36]. Actually, altered lipid metabolism in the testis is frequently associated with testicular atrophy [11].Peroxisomes are ubiquitous eukaryotic organelles that play a key role in regulating lipid homeostasis in mammals. A peroxisome proliferator induces a broad spectrum of responses such as cell proliferation, decreased apoptosis, altered estradiol levels, increased metabolism of fatty acids and eicosanoids and carcinogenesis in the rodent liver [12]. DEHP activates many genes involved in lipid metabolism including fatty acyl-CoA oxidase, 3-ketoacyl-CoA thiolase and cytochrome P450 4A1 (CYP4A1) through PPAR in the liver [3]. Although DEHP is a well-known reproductive toxicant, the mechanism of its toxicity on lipid metabolism in the testis is still unclear.Phospholipase A 2 represents a large superfamily of enzymes that catalyze the hydrolysis of phospholipids at the sn-2 positio...

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Effects of phthalate esters on lipid metabolism in various tissues, cells and organelles in mammals.

Cited by 72 publications

References 73 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.

Effects of phthalic acid esters on the liver and thyroid.

Alterations of Activities of Cytosolic Phospholipase A2 and Arachidonic Acid-Metabolizing Enzymes in Di-(2-Ethylhexyl)Phthalate-Induced Testicular Atrophy

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