Phthalic acid esters inhibit arachidonate metabolism by rat peritoneal leucocytes

Tavares, Ignatius A.; Vine, N D

doi:10.1111/j.2042-7158.1985.tb04936.x

Cited by 11 publications

(10 citation statements)

References 7 publications

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“…Dix et al and Sullivan and Cooke indicated that AA lipoxygenase pathway is involved in HCG-and LHRH-induced testosterone production by rat Leydig cells [13,46]. DEHP altered COX-2 expression levels and metabolic activity of AA in rat liver and leukocytes [28,48]. Although the effects of DEHP on AA metabolizing emzymes varied from tissue to tissue, the effects in testis were still unclear.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…We recently noticed that phthalates, known endocrine-disrupting compounds (EDCs), share a high degree of structural similarity with salicylates such as aspirin [acetyl salicylate (ASA)] that inhibit the COX-mediated conversion of AA to PGs, and previous studies have indicated that certain phthalates could interfere with the pathway (Tavares and Vine 1985). In the present study, we investigated whether known EDCs could interfere with the PG pathway in a juvenile mouse Sertoli cell line, gestational day (GD) 14.5 fetal rat testes, and in primary human mast cells.…”

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confidence: 99%

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

Kristensen

Skalkam

Audouze

et al. 2011

Environ Health Perspect

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BackgroundProstaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.Objectives and MethodsUsing cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.ResultsWe found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator–activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.ConclusionOur findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.

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“…动植物或肉制品中检测出 [3] 。在台湾，PAEs 广泛的存在于河水、底泥和土壤中 [4] ，并发现其累积在鱼体内 [5] 。许多实验发现，PAEs 因水溶性(solubility)和降解性低，且亲脂性(hydrophobicity)和吸附性高，可以在陆地和水域环境的食物链中发生生物累积 [2] ，造成不正常的性发育和降低生殖功能而干扰繁殖和族群大小 [6][7][8][9] 。Autian 研究指出，当母体内累积过多浓度的 PAE 会造成男性胎儿雌性化现象 [10] 。动物毒性试验研究发现，某些 PAEs 对鼠類和大部份哺乳动物具有肝脏和肾脏毒害性 [11] ；PAEs 对鱼类(例如虹鳟、大西洋鲑鱼等)具强烈之生物浓缩作用，易累积至生物体内之脂肪层，长期下来会造成水中生物遗传因子突变、生物体畸形、生理异常等 [12,13] …”

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Development of Ecotoxicogenomic Biomarkers on the Freshwater Shrimp (Neocaridina denticulate) Following Short-Term Exposure to Dipropyl Phthalate

蔡¹

2013

IJE

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Phthalate esters (PAEs), which are widely used in industrial chemicals that serve as important additives to impart flexibility to polyvinyl chloride resins and have become widely diffused in the environment, are considered to be endocrine disrupting chemicals (EDCs). In order to assess the toxicity of PAE to aquatic crustacean, after shrimps (Neocaridina denticulate) were short-term exposed to a sublethal concentration (50 mg/L) of dipropyl phthalate (DPrP), the differential expression genes were isolated and identified using suppression subtractive hybridization (SSH) on the samples prepared from the whole individual. There were 71 unique expressed sequence tags (ESTs) which were identified by homology with data-based sequences, including 23 ESTs corresponded to known genes and 48 ESTs with unknown function. The known genes could be divided into nine classes on the basis of physiological function: genes related to ribosomal, metabolism, immune and structural molecules, concerning the translation-related molecules, involved respiration and signaling, and responding to signaling and vision. By comparing the level of gene transcription in DPrP-treated group vs. non-treated group using semi-quantitative RT-PCR, we found that six of twelve selected genes were significantly up-regulated following exposure to DPrP at high concentration (50 mg/L), including two immune-related genes, one metabolism-related gene and 3 unknown genes. There were eight genes which are significantly responding to DPrP treatment at 1.0 mg/L, including five up-regulated genes (four known genes and one unknown gene) and three down-regulated unknown genes. After exposure to 0.5 mg/L of DPrP, only four genes (three known genes and one unknown gene) were affected and their mRNA levels increased significantly. These results suggest that N. denticulate may be harmed via the change of the globally physiological function following exposure in non-lethal PAE-polluted aquatic environment; in addition, the ESTs derived from N. denticulate can be used for studying the ecotoxicological effect of other pollutants in the aquatic environment.

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Phthalic acid esters inhibit arachidonate metabolism by rat peritoneal leucocytes

Cited by 11 publications

References 7 publications

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

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

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

Development of Ecotoxicogenomic Biomarkers on the Freshwater Shrimp (Neocaridina denticulate) Following Short-Term Exposure to Dipropyl Phthalate

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