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Chemical Compound Review:

Mehp 2-(2- ethylhexoxycarbonyl)benzoic acid

Synonyms: MEHP-d4, BAR 1, SureCN472689, CCRIS 1742, AG-F-54460, ...

Heindel, J.J. et al., Barry, Y.A. et al., Kirby, P.E. et al., Phillips, B.J. et al., Main, K.M. et al., et al.

Schlezinger, Howard, Hurst, Emberley, Waxman, Webster, Sherr, Dalgaard, Nellemann, Lam, Sørensen, Ladefoged, Kleinsasser, Harréus, Kastenbauer, Wallner, Sassen, Staudenmaier, Rettenmeier, Richburg, Nañez, Main, Mortensen, Kaleva, Boisen, Damgaard, Chellakooty, Schmidt, Suomi, Virtanen, Petersen, Andersson, Toppari, Skakkebaek, Mizrak, Bogerd, Lopez-Casas, Párraga, Del Mazo, de Rooij, Latini, De Felice, Presta, Del Vecchio, Paris, Ruggieri, Mazzeo, Weuve, Sánchez, Calafat, Schettler, Green, Hu, Hauser, Richburg, Nañez, Williams, Embree, Boekelheide,

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Disease relevance of MONO-2-ETHYLHEXYL PHTHALATE

Hypotension and cardiac arrest in rats after infusion of mono(2-ethylhexyl) phthalate (MEHP), a contaminant of stored blood [1].
Circulating levels of mono(2-ethylhexyl)phthalate are only 20- to 35-fold lower in patients undergoing cardiac operations than the level of mono(2-ethylhexyl)phthalate causing a 50% reduction in developed contractile force and arrhythmias in an in vitro human atrial trabecular preparation [2].
Serum concentrations of DEHP and its major derivatives mono-(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH) and phthalic acid (PA) were determined in uraemic patients before and after a haemodialysis session and compared with the occurrence and intensity of pruritus in these patients [3].
A single oral dose of 400 mg/kg body weight of mono(2-ethylhexyl)phthalate (MEHP), the testis toxic metabolite of di(2-ethylhexyl)phthalate, was given to 28-day-old male Wistar rats and the testis toxic effects were investigated 3,6, and 12 h after exposure [4].
Neither DEHP, MEHP, nor EH exhibited any significant mutagenic activity in strains TA-98, TA-100, TA-1535, TA-1537, and TA-1538 in the Ames test or when tested in the L5178Y TK+/- mouse lymphoma cell mutagenicity assay [5].

High impact information on MONO-2-ETHYLHEXYL PHTHALATE

Clofibric acid, mono(2-ethylhexyl)phthalate, and Wy-14,643 induced enzymes indicative of peroxisomal proliferation in primary rat hepatocyte cultures, but not in two human hepatocyte cultures [6].
Environmental and endogenous peroxisome proliferator-activated receptor gamma agonists induce bone marrow B cell growth arrest and apoptosis: interactions between mono(2-ethylhexyl)phthalate, 9-cis-retinoic acid, and 15-deoxy-Delta12,14-prostaglandin J2 [7].
To test the role of the Fas system in toxicant-induced germ cell apoptosis, mice were exposed to either a Sertoli cell- or germ cell-specific toxicant [mono-(2-ethylhexyl)phthalate (MEHP; 1 g/kg) or 5 Gy radiation, respectively] [8].
Incubation of hepatocytes with the PPs mono(2-ethylhexyl)phthalate (MEHP), nafenopin and [4-chloro-6-(2,3- xylidino)-2-pyrimidylthio]acetic acid (Wy-14,643) decreased dye coupling of the hepatocytes [9].
We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)] [10].

Chemical compound and disease context of MONO-2-ETHYLHEXYL PHTHALATE

DEHP, MEHP, 2-EH, and PA exhibited no mutagenicity in any of the strains of Salmonella typhimurium tested, with or without S9 metabolic activation [11].

Biological context of MONO-2-ETHYLHEXYL PHTHALATE

In CHO cells, the clastogenicity of MEHP was unaffected by the presence of an exogenous metabolic activation system (S-9 mix) [12].
MEHP-positive newborns showed a significantly lower gestational age compared with MEHP-negative infants (p = 0.033) [13].
Since chromosome damage was observed only at cytotoxic concentrations, it is suggested that damage to lysosomal membranes and the release of endonucleases may be responsible for the observed clastogenicity of MEHP in vitro [12].
By subtractive cDNA libraries we identified genes deregulated as response to MEHP in primary cultures of mouse Sertoli cells [14].
CAPD fluids in PVC bags contain low concentrations of DEHP and its hydrolysis product mono-(2-ethylhexyl)phthalate (MEHP) [15].

Anatomical context of MONO-2-ETHYLHEXYL PHTHALATE

No evidence of an increase in peroxisome numbers or of induction of marker enzymes was found in CHO cells treated with MEHP for up to 72 hr [12].
We found detectable cord blood DEHP and/or MEHP concentrations in 88.1% of the samples [13].
Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription [16].
Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056) [10].
Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells [17].

Associations of MONO-2-ETHYLHEXYL PHTHALATE with other chemical compounds

The results show that the PPs nafenopin, MEHP and Wy-14,643 decrease IC between cultured hepatocytes [9].
In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner [16].
OBJECTIVE: We previously demonstrated that among 54 infants in neonatal intensive care units, exposure to polyvinyl chloride plastic medical devices containing the plasticizer di(2-ethylhexyl) phthalate (DEHP) is associated with urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP) , a DEHP metabolite [18].
Di(2-ethylhexyl)phthalate and its principal metabolite, mono(2-ethylhexyl)phthalate, are contaminants of blood that are extracted on contact with polyvinylchloride surfaces, such as blood collection bags and tubing used in cardiopulmonary bypass [2].
Mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of the testicular toxicant di(2-ethylhexyl) phthalate, inhibits FSH-stimulated rat Sertoli cell cAMP accumulation, stimulates basal lactate production, and decreases intracellular ATP levels in vitro [19].

Gene context of MONO-2-ETHYLHEXYL PHTHALATE

The contribution of Fas-mediated signaling is especially evident in the initiation of germ cell apoptosis after mono-(2-ethylhexyl)phthalate (MEHP)-induced Sertoli cell injury [20].
In previous work, we demonstrated that the incidence of germ cell apoptosis after MEHP exposure is significantly reduced in B6.SMNC3H-Fas(gld,gld) (gld) mice that express a dysfunctional form of the FasL protein (the associated ligand that activates Fas) [20].
We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell [16].
The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (beta-oxidation; cyanide-insensitive palmitoyl CoA oxidase) and concomitant increases in the number of peroxisomes [21].
Hence, 1,3-dinitrobenzene (1,3-DNB; 10(-6) - 10(-4) M), and mono-(2-ethylhexyl)phthalate (MEHP; 10(-8) - 10(-4) M) were tested in rat Sertoli cell cultures [22].

Analytical, diagnostic and therapeutic context of MONO-2-ETHYLHEXYL PHTHALATE

We measured serum DEHP and MEHP concentrations in the cord blood of 84 consecutive newborns by high-performance liquid chromatography [13].
For example, mono(2-ethylhexyl)phthalate was more potent than mono(1-ethylhexyl)phthalate, and this was also observed after oral administration of the two isomers to rats for seven days [23].
Mono(2-ethylhexyl)phthalate exhibits genotoxic effects in human lymphocytes and mucosal cells of the upper aerodigestive tract in the comet assay [24].
In addition, the mitotic index, determined from 100 cells per animal, was unaffected by DEHP, MEHP, or EH [25].

References

Hypotension and cardiac arrest in rats after infusion of mono(2-ethylhexyl) phthalate (MEHP), a contaminant of stored blood. Rock, G., Labow, R.S., Franklin, C., Burnett, R., Tocchi, M. N. Engl. J. Med. (1987) [Pubmed]
Perioperative exposure to plasticizers in patients undergoing cardiopulmonary bypass. Barry, Y.A., Labow, R.S., Keon, W.J., Tocchi, M., Rock, G. J. Thorac. Cardiovasc. Surg. (1989) [Pubmed]
Uraemic pruritus and exposure to di(2-ethylhexyl) phthalate (DEHP) in haemodialysis patients. Mettang, T., Thomas, S., Kiefer, T., Fischer, F.P., Kuhlmann, U., Wodarz, R., Rettenmeier, A.W. Nephrol. Dial. Transplant. (1996) [Pubmed]
The acute effects of mono(2-ethylhexyl)phthalate (MEHP) on testes of prepubertal Wistar rats. Dalgaard, M., Nellemann, C., Lam, H.R., Sørensen, I.K., Ladefoged, O. Toxicol. Lett. (2001) [Pubmed]
Evaluation of di-(2-ethylhexyl)phthalate and its major metabolites in the Ames test and L5178Y mouse lymphoma mutagenicity assay. Kirby, P.E., Pizzarello, R.F., Lawlor, T.E., Haworth, S.R., Hodgson, J.R. Environmental mutagenesis. (1983) [Pubmed]
Use of primary cultures of human hepatocytes in toxicology studies. Butterworth, B.E., Smith-Oliver, T., Earle, L., Loury, D.J., White, R.D., Doolittle, D.J., Working, P.K., Cattley, R.C., Jirtle, R., Michalopoulos, G. Cancer Res. (1989) [Pubmed]
Environmental and endogenous peroxisome proliferator-activated receptor gamma agonists induce bone marrow B cell growth arrest and apoptosis: interactions between mono(2-ethylhexyl)phthalate, 9-cis-retinoic acid, and 15-deoxy-Delta12,14-prostaglandin J2. Schlezinger, J.J., Howard, G.J., Hurst, C.H., Emberley, J.K., Waxman, D.J., Webster, T., Sherr, D.H. J. Immunol. (2004) [Pubmed]
Sensitivity of testicular germ cells to toxicant-induced apoptosis in gld mice that express a nonfunctional form of Fas ligand. Richburg, J.H., Nañez, A., Williams, L.R., Embree, M.E., Boekelheide, K. Endocrinology (2000) [Pubmed]
Inhibition of intercellular communication of rat hepatocytes by nafenopin: involvement of protein kinase C. Leibold, E., Greim, H., Schwarz, L.R. Carcinogenesis (1994) [Pubmed]
Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Main, K.M., Mortensen, G.K., Kaleva, M.M., Boisen, K.A., Damgaard, I.N., Chellakooty, M., Schmidt, I.M., Suomi, A.M., Virtanen, H.E., Petersen, D.V., Andersson, A.M., Toppari, J., Skakkebaek, N.E. Environ. Health Perspect. (2006) [Pubmed]
Mutagenicity evaluation of phthalic acid esters and metabolites in Salmonella typhimurium cultures. Agarwal, D.K., Lawrence, W.H., Nunez, L.J., Autian, J. Journal of toxicology and environmental health. (1985) [Pubmed]
Studies on the genetic effects of phthalic acid esters on cells in culture. Phillips, B.J., Anderson, D., Gangolli, S.D. Environ. Health Perspect. (1986) [Pubmed]
In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy. Latini, G., De Felice, C., Presta, G., Del Vecchio, A., Paris, I., Ruggieri, F., Mazzeo, P. Environ. Health Perspect. (2003) [Pubmed]
Expression of stress inducible protein 1 (Stip1) in the mouse testis. Mizrak, S.C., Bogerd, J., Lopez-Casas, P.P., Párraga, M., Del Mazo, J., de Rooij, D.G. Mol. Reprod. Dev. (2006) [Pubmed]
Exposure of patients to phthalates from polyvinyl chloride tubes and bags during dialysis. Nässberger, L., Arbin, A., Ostelius, J. Nephron (1987) [Pubmed]
Mechanisms of phthalate ester toxicity in the female reproductive system. Lovekamp-Swan, T., Davis, B.J. Environ. Health Perspect. (2003) [Pubmed]
Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells. Lloyd, S.C., Foster, P.M. Toxicol. Appl. Pharmacol. (1988) [Pubmed]
Exposure to phthalates in neonatal intensive care unit infants: urinary concentrations of monoesters and oxidative metabolites. Weuve, J., Sánchez, B.N., Calafat, A.M., Schettler, T., Green, R.A., Hu, H., Hauser, R. Environ. Health Perspect. (2006) [Pubmed]
Phthalate ester effects on rat Sertoli cell function in vitro: effects of phthalate side chain and age of animal. Heindel, J.J., Powell, C.J. Toxicol. Appl. Pharmacol. (1992) [Pubmed]
Fas- or FasL-deficient mice display an increased sensitivity to nitrobenzene-induced testicular germ cell apoptosis. Richburg, J.H., Nañez, A. Toxicol. Lett. (2003) [Pubmed]
Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms. Elcombe, C.R., Mitchell, A.M. Environ. Health Perspect. (1986) [Pubmed]
The production of lactate and pyruvate as sensitive indices of altered rat Sertoli cell function in vitro following the addition of various testicular toxicants. Williams, J., Foster, P.M. Toxicol. Appl. Pharmacol. (1988) [Pubmed]
Structure-activity relationships for induction of peroxisomal enzyme activities by phthalate monoesters in primary rat hepatocyte cultures. Lake, B.G., Gray, T.J., Lewis, D.F., Beamand, J.A., Hodder, K.D., Purchase, R., Gangolli, S.D. Toxicology and industrial health. (1987) [Pubmed]
Mono(2-ethylhexyl)phthalate exhibits genotoxic effects in human lymphocytes and mucosal cells of the upper aerodigestive tract in the comet assay. Kleinsasser, N.H., Harréus, U.A., Kastenbauer, E.R., Wallner, B.C., Sassen, A.W., Staudenmaier, R., Rettenmeier, A.W. Toxicol. Lett. (2004) [Pubmed]
Cytogenetic evaluation of di-(2-ethylhexyl)phthalate and its major metabolites in Fischer 344 rats. Putman, D.L., Moore, W.A., Schechtman, L.M., Hodgson, J.R. Environmental mutagenesis. (1983) [Pubmed]

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