Studies on the hepatic effects of orally administered di-(2-ethylhexyl) phthalate in the rat

Lake, Brian G.; Gangolli, S.D.; Grasso, P.; Lloyd, Alun G.

doi:10.1016/0041-008x(75)90226-4

Cited by 203 publications

(49 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Perhaps one of the most striking toxicological effects of di(2-ethylhexyl) phthalate (DEHP) and related phthalate esters is their ability to elicit hepatomegaly in rodents (1,2). This phenomenon is explained, in part, by an increase in the cytoplasmic volume of the hepatocytes due to a marked proliferation of peroxisomes and smooth endoplasmic reticulum (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…This phenomenon is explained, in part, by an increase in the cytoplasmic volume of the hepatocytes due to a marked proliferation of peroxisomes and smooth endoplasmic reticulum (2,3). The increased volume density of these organelles is accompanied by induction ofperoxisomal 3-oxidation and microsomal cytochrome P452-mediated fatty acid hydroxylation (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Elcombe¹,

Mitchell²

1986

Environ Health Perspect

163

View full text Add to dashboard Cite

The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (13-oxidation; cyanide-insensitive palmitoyl CoA oxidase) and concomitant increases in the number of peroxisomes. Similar treatment of cultured guinea pig, marmoset, or human hepatocytes revealed little or no effect of MEHP. In order to eliminate possible confounding influences of biotransformation, the proximate peroxisome proliferator(s) derived from MEHP have been identified. Using cultured hepatocytes these agents were found to be metabolite VI [mono(2-ethyl-5-oxohexyl) phthalate] and metabolite IX [mono(2-ethyl-5-hydroxyhexyl) phthalate]. The addition of these "active" metabolites to cultured guinea pig, marmoset, or human hepatocytes again revealed little effect upon peroxisomes or related enzyme activities (peroxisomal 1-oxidation or microsomal lauric acid hydroxylation). These studies demonstrate a marked species difference in the response of hepatocytes to MEHP-elicited peroxisome proliferation. Preliminary studies have also suggested that peroxisome proliferation due to MEHP may be due to an initial biochemical lesion of fatty acid metabolism.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Elcombe¹,

Mitchell²

1986

Environ Health Perspect

163

View full text Add to dashboard Cite

show abstract

“…There have been many reports on the hepatotoxicity, testicular atrophy, teratogenicity and carcinogenicity as related to PEs. [1][2][3][4][5][6] Recently, di-n-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) have in particular been attracting attention as being suspects in disrupting the endocrine system. [7][8][9][10] PEs are considered to be biodegradable and having low bioaccumulation.…”

mentioning

confidence: 99%

Phthalate Esters Detected in Various Water Samples and Biodegradation of the Phthalates by Microbes Isolated from River Water.

Hashizume

Nanya

Toda

et al. 2002

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Phthalate esters (PEs), especially di-n-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) were detected in various water samples such as river water, well water and tap water. On degradation tests of PEs, Tempaku River water degraded almost 100% of diethyl phthalate (DEP), di-isobutyl phthalate and DBP, and approximately 70% of DEHP. All eight isolates from Tempaku River water (R1-R7, D1) did not degrade dimethyl phthalate (DMP), but showed biodegrading ability for the other PEs. The DBP-degrading ability was particularly high for the isolates R1-R3 and D1 of Acinetobacter lwoffii. Crude enzyme solutions prepared from bacterial cells of these isolates showed a higher degrading activity for DEHP compared with that for microbiallydegradable DBP. Particularly high DEHP-degrading activity was found for crude enzyme solutions of the isolate D1. As metabolites from the river water and bacterial isolates, DMP and an unknown diester were produced from DEP. DMP, DEP, monomethyl phthalate, monobutyl phthalate (MBP) and an unknown diester were produced from DBP. DBP, DEP, DMP and an unknown diester were produced from DEHP. As metabolites by the crude enzyme solutions, DMP, MBP and an unknown diester derivative were produced from DBP. DBP, mono-(2-ethylhexyl) phthalate and an unknown diester derivative were produced from DEHP. Diesters with shortened alkyl carbon chains were also found as metabolites by the isolates and their crude enzyme solutions. The results suggest that the alkyl chains in the diesters are also decomposed in addition to monoester formation from DBP or DEHP at the first step reported for animals and some types of bacteria.

show abstract

“…Apart from the increase in size, the most noticeable change in the liver is a very marked increase in the number of peroxisomes in the hepatocytes of rats (11)(12)(13)(14), although not of guinea pigs (15) or ferrets (16). Both rats (11) and ferrets 16) show some dilation of the endoplasmic reticulum after treatment with DEHP but the main specific endoplasmic reticulum change in rats treated with DEHP, as in rats treated with clofibrate (17) is a very marked induction of the specific P-450 isoenzyme(s) catalyzing the w-oxidation of fatty acids. It has been reported that in rat hepatocytes mitochondria are increased in number by DEHP but that there is no effect in vivo on mitochondrial respiratory activity.…”

Section: Introductionmentioning

confidence: 99%

Effects of phthalic acid esters on the liver and thyroid.

Hinton¹,

Mitchell²,

Mann³

et al. 1986

Environ Health Perspect

126

View full text Add to dashboard Cite

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.

show abstract

Studies on the hepatic effects of orally administered di-(2-ethylhexyl) phthalate in the rat

Cited by 203 publications

References 29 publications

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Phthalate Esters Detected in Various Water Samples and Biodegradation of the Phthalates by Microbes Isolated from River Water.

Effects of phthalic acid esters on the liver and thyroid.

Contact Info

Product

Resources

About