The in vitro serum protein-binding characteristics of bis-(2-ethylhexyl) phthalate and its principal metabolite, mono-(2-ethylhexyl) phthalate.

Griffiths, William C.; Camara, Paul; Saritelli, Ann L.; Gentile, Joseph

doi:10.1289/ehp.8877151

Cited by 25 publications

(12 citation statements)

References 25 publications

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“…MEHP accumulation is of concern because MEHP is 20 times more toxic than DEHP in rats 11. Additionally, MEHP has a longer plasma half-life due to its ability to bind to serum proteins, specifically to human serum albumin 12,13. Due to its lipophilic characteristics, DEHP also exerts many biochemical effects such as decreasing its own metabolism by inhibiting serum arylesterase activity levels 14.…”

Section: Discussionmentioning

confidence: 99%

Phthalate Esters Used as Plasticizers in Packed Red Blood Cell Storage Bags May Lead to Progressive Toxin Exposure and the Release of Pro‐Inflammatory Cytokines

Rael

Bar-Or

Ambruso³

et al. 2009

Oxidative Medicine and Cellular Longevity

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Phthalate esters (PE's) are plasticizers used to soften PVC-based medical devices. PE's are the most abundant man-made pollutants and increase the risk of developing an allergic respiratory disease or a malignancy. The leaching of PE's in donated packed red blood cells (PRBC) during storage was assessed. PRBC transfusion bags containing CPD/AS-1 (ADSOL) buffer were analyzed. Samples were collected on storage day 1 and day 42. Two PE's, di-(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP), were measured by liquid chromatography coupled to mass spectrometry (LCMS). Interleukin-8 (IL-8) was measured by standard ELISA techniques. DEHP significantly increased from 34.3 µM (±20.0 SD) on day 1 to 433.2 µM (±131.2 SD) on day 42, a 12.6-fold increase. Similarly, MEHP significantly increased from 3.7 µM (±2.8 SD) on day 1 to 74.0 µM (±19.1 SD) on day 42, a 20.2-fold increase. Also, DEHP and MEHP increased the release of IL-8 from human umbilical vein endothelial cells (HUVEC). The transfusion of older units of PRBC could lead to an accumulation of PE's possibly resulting in inflammation and other effects. This accumulation could be exacerbated due to the decreased metabolism of PE's since trauma patients have a lower esterase activity, the enzymes responsible for metabolizing PE's. The effect of oxidative stress caused by PE's is discussed as a potential mechanism for increases in inflammation caused by older units of PRBC.

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Section: Discussionmentioning

confidence: 99%

Phthalate Esters Used as Plasticizers in Packed Red Blood Cell Storage Bags May Lead to Progressive Toxin Exposure and the Release of Pro‐Inflammatory Cytokines

Rael

Bar-Or

Ambruso³

et al. 2009

Oxidative Medicine and Cellular Longevity

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“…MEHP is negatively charged and by that cannot be taken up into the cells in an in vitro model cultured without fetal calf serum (FCS) 80 , 81 . Moreover, the systemic availability of DEHP is 50–100 times higher in humans than in marmosets and rodents 20 .…”

Section: Methodsmentioning

confidence: 99%

DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS-adipocytes

Schaedlich

Gebauer

Hunger

et al. 2018

Sci Rep

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DEHP is a plasticizer which has been used in plastic products of everyday use for decades. Studies in mice and murine cell culture models identified DEHP as an endocrine disruptor that may also act as an obesogen. As this is of high concern in respect of the worldwide obesity epidemic, our aim is the translation of these findings into a human model system. On the basis of DOHaD, we investigated the influence of an environmentally relevant dose of DEHP [50 µg/ml] on adipogenesis in the human cell culture model SGBS. Pre-adipocytes were exposed to DEHP and differentiated into mature adipocytes. At different stages of differentiation, markers of adipogenesis like GLUT4, FABP4, LPL and PPARs, and of signaling pathways like AMPK/ACC2, JAK/STAT and MAPK were analyzed. Functional markers like adipokine secretion and triglyceride content as well as ROS production were measured in mature adipocytes. We found significantly lower expression levels of adipogenic markers, a reduction in lipid accumulation, higher leptin- and reduced adiponectin levels in the supernatant of treated adipocytes. Moreover, ROS production was significantly elevated after DEHP-exposure. In conclusion, DEHP led to lower grade of adipogenic differentiation in human SGBS-adipocytes under the chosen conditions.

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“…Besides this, DEHP exposure has been correlated with metabolic disorders mainly via the PPAR signaling pathway. A study by Griffiths et al (1988) showed that DEHP partly binds to lipoproteins as well as lipids, owing to its lipophilic character. In this study we used DEHP instead of the active metabolite MEHP.…”

Section: Discussionmentioning

confidence: 99%

“…They have different lipophilic characteristics and they differ in bioavailibilty. A study by Griffiths et al (1988) showed that DEHP partly binds to lipoproteins as well as lipids, owing to its lipophilic character. MEHP has diminished lipid solubility due to its free carboxyl group and greater polarity, and binds to albumin analogues.…”

Section: Discussionmentioning

confidence: 99%

Impact of di‐ethylhexylphthalate exposure on metabolic programming in P19 ECC‐derived cardiomyocytes

Schaedlich

Schmidt

Kwong

et al. 2014

J of Applied Toxicology

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Di(2-ethylhexyl)phthalate (DEHP) is the most common plasticizer in plastic devices of everyday use. It is a ubiquitous environmental contaminant and primarily known to impair male gonadal development and fertility. Studies concerning the long-term effects of prenatal DEHP exposure on certain diseases [The Developmental Origins of Health and Disease paradigm (DOHaD) hypothesis] are scarce although it is proven that DEHP crosses the placenta. Rising environmental pollution during the last centuries coincides with an increasing prevalence of cardiovascular and metabolic diseases. We have investigated the effects of an early embryonic DEHP exposure at different developmental stages on cardiomyogenesis. We used an in-vitro model, the murine P19 embryonic carcinoma cell line (P19 ECC), mimicking early embryonic stages up to differentiated beating cardiomyocytes. P19 ECC were exposed to DEHP (5, 50, 100 µg ml(-1)) at the undifferentiated stage for 5 days and subsequently differentiated to beating cardiomyocytes. We analyzed the expression of metabolic (Pparg1, Fabp4 and Glut4), cardiac (Myh6, Gja1) and methylation (Dnmt1, Dnmt3a) marker genes by quantitative real-time PCR (qRT-PCR), beating rate and the differentiation velocity of the cells. The methylation status of Pparg1, Ppara and Glut4 was investigated by pyrosequencing. DEHP significantly altered the expression of all investigated genes. The beating rate and differentiation velocity were accelerated. Exposure to DEHP led to small but statistically significant increases in methylation of specific CpGs within Ppara and Pparg1, which otherwise were generally hypomethylated, but methylation of Glut4 was unaltered. Early DEHP exposure of P19 ECC alters the expression of genes associated with cellular metabolism and the functional features of cardiomyocytes.

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The in vitro serum protein-binding characteristics of bis-(2-ethylhexyl) phthalate and its principal metabolite, mono-(2-ethylhexyl) phthalate.

Cited by 25 publications

References 25 publications

Phthalate Esters Used as Plasticizers in Packed Red Blood Cell Storage Bags May Lead to Progressive Toxin Exposure and the Release of Pro‐Inflammatory Cytokines

Phthalate Esters Used as Plasticizers in Packed Red Blood Cell Storage Bags May Lead to Progressive Toxin Exposure and the Release of Pro‐Inflammatory Cytokines

DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS-adipocytes

Impact of di‐ethylhexylphthalate exposure on metabolic programming in P19 ECC‐derived cardiomyocytes

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