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

Abstract

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...

Maternal Di-(2-ethylhexyl)-phthalate Exposure Influences Essential Fatty Acid Homeostasis in Rat Placenta

“…They mediate the metabolism of long chain EFAs to eicosanoids, which can be further converted to other important bioactive molecules critical for fetal development, such as PG, thromboxane and prostacyclin [26]. The current study demonstrated that the expression of CYP4A1, the major CYP4A isoform present in rat placenta [12], was significantly induced in both the LAB and JXN (Figure 3), consistent with previous reports in mouse liver [27] and testis [28]. The induction pattern of CYP4A1 correlated with the observed changes of PPARα by DEHP exposure (Figure 1), which might reflect the fact that CYP4A isoforms are under transcriptional control of PPARs, particularly PPARα [29].…”

The combined effects of DEHP and PCBs on phospholipase in the livers of mice

“…There are four major classes of phospholipase, termed A, B, C, and D, those are distinguished by the type of reaction that they catalyze. A previous study showed that DEHP (100 and 1,000 mg/kg, 5 days) administration caused a significant reduction in the activity of cytosolic PLA in the testes of prepubertal rats (Kim et al, ). In our study, the expression of PLA was down‐regulated at both the mRNA and protein levels in male mice after combined treatment with DEHP and Aroclor 1254.…”

Deciphering Diseases and Biological Targets for Environmental Chemicals using Toxicogenomics Networks

“…Using our approach, several proteins were identified as being associated with DEHP (Table 2). Cysteine dioxygenase type I (CD01) and peroxisome proliferator-activated receptor alpha (PPARA), the two top scoring proteins, are already known in the CTD and from the literature [37]–[38] as molecular targets for DEHP. Six other high ranking proteins are new potential DEHP molecular targets which are not recorded in the CTD (thus not input data).…”