Exposure of patients to di(2-ethylhexy)phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy.

The plasticizer di(2-ethylhexyl)phthalate (DEHP) is often used for PVC medical devices, that are also largely used for intensive care medical treatments, like extracorporeal membrane oxygenation (ECMO) therapy. Due to the toxicological potential of DEHP, the inner exposure of patients with this plasticizer is a strong matter of concern as many studies have shown a high leaching potential of DEHP into blood. In this study, the inner DEHP exposure of patients undergoing ECMO treatment was investigated. The determined DEHP blood levels of ECMO patients and the patients of the control group ranged from 31.5 to 1009 µg/L (median 156.0 µg/L) and from 19.4 to 75.3 µg/L (median 36.4 µg/L), respectively. MEHP blood levels were determined to range from < LOD to 475 µg/L (median 15.9 µg/L) in ECMO patients and from < LOD to 9.9 µg/L (median 3.7 µg/L) in the control group patients, respectively. Increased DEHP exposure was associated with the number of cannulas and membranes of the ECMO setting, whereas residual diuresis decreased the exposure. Due to the suspected toxicological potential of DEHP, its use in medical devices should be further investigated, in particular for ICU patients with long-term exposure to PVC, like in ECMO therapy.

Maternal di-(2-ethylhexyl) phthalate exposure alters hepatic insulin signal transduction and glucoregulatory events in rat F1 male offspring.

Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with endocrine disrupting properties. Its widespread use resulted in constant human exposure including fetal development and postnatal life. Epidemiological and experimental data have shown that DEHP has a negative influence on glucose homeostasis. However, the evidence regarding the effect of maternal DEHP exposure on hepatic glucose homeostasis is scarce. Hence, we investigated whether DEHP exposure during gestation and lactation disrupts glucose homeostasis in the rat F1 male offspring at adulthood. Pregnant rats were divided into three groups and administered with DEHP (10 and 100 mg/kg/day) or olive oil from gestational day 9 to postnatal day 21 (lactation period) through oral gavage. DEHP-exposed offspring exhibited hyperglycemia, impaired glucose and insulin tolerances along with hyperinsulinemia at postnatal day 80. DEHP exposure significantly reduced the levels of insulin signaling molecules such as insulin receptors, IRS1, Akt and its phosphorylated forms. GSK3ß and FoxO1 proteins increased in DEHP-exposed groups whereas its phosphorylated forms decreased. Treated groups showed decreased glycogen synthase activity and glycogen concentration. Glucose-6-phosphatase and phosphoenolpyruvate carboxykinase mRNA level and enzyme activity increased in DEHP-treated groups. The interaction between FoxO1-glucose-6-phosphatase and FoxO1-phosphoenolpyruvate carboxykinase was also increased. This study suggests that DEHP exposure impairs insulin signal transduction and alters glucoregulatory events leading to the development of type 2 diabetes in F1 male offspring.

Plasticizer, di(2-ethylhexyl)phthalate (DEHP) enhances cockroach allergen extract-driven airway inflammation by enhancing pulmonary Th2 as well as Th17 immune responses in mice.

In recent decades, there has been a gradual increase in the prevalence of asthma. Various factors including environmental pollutants have contributed to this phenomenon. Plasticizer, di(2-ethylhexyl)phthalate (DEHP) is one of the commonest environmental pollutants due to its association with plastic products. DEHP gets released from plastic products easily leading to respiratory exposure in humans. As a consequence, DEHP is associated with allergic asthma in humans and animals. DEHP is reported to act as an adjuvant in ovalbumin-induced mouse models of asthma at high doses. However, these studies mostly looked into the role of DEHP on Th2 cytokines/eosinophilic inflammation without investigating the role of airway epithelial cells (AECs)/dendritic cells (DCs)/Th17 cells. Its adjuvant activity with natural allergens such as cockroach allergens at tolerable daily intake needs to be explored. Cockroach allergens and DEHP may be inhaled together due to their coexistence in work place as well as household environments. Therefore, effect of DEHP was assessed in cockroach allergens extract (CE)-induced mouse model of asthma. Airway inflammation, histopathology, mucus secretion, and immune responses related to Th2/Th17/DCs and AECs were assessed in mice with DEHP exposure alone and in combination with CE. Our study shows that DEHP converts CE-induced eosinophilic inflammation into mixed granulocytic inflammation by promoting Th2 as well as Th17 immune responses. This was probably due to downregulation of E-cadherin in AECs, and enhancement of costimulatory molecules (MHCII/CD86/CD40)/pro-inflammatory cytokines (IL-6/MCP-1) in DCs by DEHP. This suggests that DEHP facilitates development of mixed granulocytic airway inflammation in the presence of a natural allergen.

The Impact of Di(2-ethylhexyl)phthalate on Cancer Progression.

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer, mainly serves as an additive to render polyvinyl chloride (PVC) soft and flexible. PVC plastics have become ubiquitous in our modern society. Yet, the leaching of DEHP from PVC-based consumables ultimately results in the deposition in certain tissues via inadvertent applications. Health risks for human populations exposed to DEHP has been assumed by studies on rodents and other species, including the DEHP-induced developmental dysregulation, reproductive impairments, tumorigenesis, and diseases in a transgenerational manner. In this review, we comprehensively summarize the accumulated literature regarding the multifaceted roles of DEHP in the activation of the nuclear receptors, the alteration of the redox homeostasis, epigenetic modifications and the acquisition of chemoresistance.

Antitumour evaluation of di-(2-ethylhexyl) phthalate (DEHP) isolated from Calotropis gigantea L. flower.

The objective of the study is to explore the anticancer activity of di-(2-ethylhexyl) phthalate (DEHP) isolated from Calotropis gigantea flower against Ehrlich ascites carcinoma cells (EAC) in Swiss albino mice. The activity of DEHP was evaluated at doses of 10, 20 and 40 mg kg-1 body mass applied intraperitoneally. DEHP showed a significant decrease in viable cell count (p < 0.05), mass gain (due to tumour burden) and elevated the life span of EAC cell bearing mice. Altered hematological profiles such as RBC, hemoglobin, WBC and differential count were reverted to normal levels in DEHP-treated mice. DEHP also brought back altered biochemical parameters (glucose, cholesterol, triglycerides, blood urea, SALP and SGOT) to normal level. Results of this study indicate that DEHP show potent dose dependent antitumour activity against EAC in vivo.

The effect of the plasticizer diethylhexyl phthalate on transport activity and expression of P-glycoprotein in parental and doxo-resistant human sarcoma cell lines.

Multidrug resistance (MDR) to cancer therapy is frequently associated with the over-expression of the multidrug transporter MDR1 gene product P-glycoprotein (Pgp) in several types of human tumours. Various chemosensitizers have been used to inhibit Pgp activity but toxicity limits their clinical application. Di(2-ethylhexyl)phthalate (DEHP) is a plasticizer that is released from polyvinyl chloride (PVC) medical devices. Therefore, cancer patients undertaking chemotherapy are exposed to a clinically important amount of DEHP through blood and blood component transfusions, apheresis products, intravenous chemotherapy, parenteral nutrition and other medical treatments. The present study was designed to investigate the effects of DEHP on transport activity and expression of Pgp in order to evaluate its potential use as a chemosensitizer in cancer therapy. Human doxorubicin (doxo) resistant sarcoma cells (MES-SA/Dx5) that over-express Pgp were treated with different doses of doxo (2, 4 and 8 µM) in the presence or absence of various concentrations of DEHP (3, 6 and 12 µM) that were clinically achievable in vivo. Our results show that co-treatment with 2, 4 and 8 µM doxo in the presence of the lowest concentration of DEHP (3 µM) enhanced significantly doxo accumulation in MES-SA/Dx5 cells and, consistently increased the sensitivity to doxo, when compared to controls receiving only doxo. In contrast, higher DEHP concentrations (6 and 12 µM) induced MES-SA/Dx5 to extrude doxo decreasing doxo cytotoxicity toward resistant cells below control values. These results are consistent with the increase in Pgp expression levels in parental MES-SA cells treated with 3, 6 and 12 µM DEHP for 24 h and compared to untreated controls. All in all, these findings suggest a potential clinical application of DEHP as a chemosensitizer to improve effectiveness of the antineoplastic drugs in MDR human tumours.

Inhibition by catechol and di(2-ethylhexyl)phthalate of pancreatic carcinogenesis after initiation with N-nitrosobis(2-hydroxypropyl)amine in Syrian hamsters.

The effects of dietary administration of catechol (CC), paramethylcatechol (PMC) and di(2-ethylhexyl)phthalate (DEHP) were compared with that of butylated hydroxyanisole (BHA) in Syrian hamsters initiated with N-nitrosobis(2-hydroxypropyl)amine (BHP). Development of pancreatic atypical hyperplasias and adenocarcinomas in terms of combined multiplicity was significantly reduced by CC and DEHP. A similar slight but non-significant tendency was observed for BHA, while PMC was without effect. No statistically significant reduction of liver or gall bladder lesions was observed. The results thus suggest that both antioxidant and peroxisome proliferator categories of agents can inhibit pancreatic carcinogenesis in hamsters.