Low dose monoethyl phthalate (MEP) exposure triggers proliferation by activating PDX-1 at 1.1B4 human pancreatic beta cells

Güven, Cengiz; Dal, Fulya; Ahbab, Müfide Aydoğan; Taşkın, Eylem; Ahbab, Süleyman; Çınar, Suzan; Ekmekçi, Sema Sırma; Güleç, Çağrı; Abacı, Neslihan; Akçakaya, Handan

doi:10.1016/j.fct.2016.04.023

Cited by 18 publications

(13 citation statements)

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“…More recent rodent models (8, 36) suggest that the hypolipidemic effect of DEHP may arise through its interactions with peroxisome proliferator-activated receptor-α (PPAR-α), a ligand-activated transcription factor that can decrease production of LDL-C and triglycerides, and upregulate HDL-C levels through its roles in lipid oxidation and fatty acid synthesis (37, 38). Likewise, our finding that higher peripubertal MEP was associated with lower total cholesterol and LDL-C could be explained by the fact that MEP is an estrogenic compound that may act as a PPAR-γ agonist (39) to reduce circulating lipid levels by promoting uptake and storage of free fatty acids in adipose tissue (40). …”

Section: Discussionmentioning

confidence: 85%

Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth

Perng

Watkins

Cantoral³

et al. 2017

Environmental Research

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Animal models indicate that endocrine disrupting chemicals (EDCs) affect circulating lipid concentrations by interfering with hepatic fatty acid oxidation. Little is known of the relationship between EDC exposure and lipid profile in humans. We measured bisphenol A (BPA) and 9 phthalate metabolites in maternal urine collected at up to three time points during pregnancy as a measure of in utero exposure, and in the child’s urine at 8–14 years as a measure of concurrent, peripubertal exposure among 248 participants of a Mexico City pre-birth cohort. We used linear regression to examine relations of BPA and phthalate exposure with peripubertal serum lipids, while also adjusting for child age, sex, and specific gravity. While in utero EDC exposure was not associated with lipid profile, higher concurrent levels of mono-3-carboxypropyl phthalate (MCPP), monoethyl phthalate (MEP), and dibutyl phthalate metabolites (DBP) corresponded with lower total cholesterol and low-density lipoprotein (LDL-C) in boys; e.g., an interquartile range increment in MCPP corresponded with 7.4% (2.0%, 12.8%) lower total cholesterol and 12.7% (3.8%, 21.6%) lower LDL-C. In girls, higher urinary di-2-ethylhexyl phthalate metabolites (ΣDEHP) correlated with lower LDL-C (−7.9% [−15.4%, −0.4%]). Additional longitudinal research is needed to determine whether these associations persist beyond adolescence.

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Section: Discussionmentioning

confidence: 85%

Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth

Perng

Watkins

Cantoral³

et al. 2017

Environmental Research

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“…MEP may work to increase insulin resistance through its posited estrogenic activity [ 46 ]. Urinary concentrations of another EDC with estrogenic activity, bisphenol A, have been shown to be positively associated with glucose levels in human populations [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic

et al. 2018

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BackgroundSubfertile women are at increased risk of glucose intolerance in pregnancy. Based on epidemiologic studies, exposure to certain phthalates is associated with diabetes, elevated glucose, and increased insulin resistance.ObjectivesTo evaluate the association between urinary phthalate metabolites and pregnancy glucose levels in women seeking medically assisted reproduction.MethodsWe evaluated 245 women participating in a prospective cohort study based at a large fertility clinic who delivered live births and had data on pregnancy urinary phthalate metabolite concentrations and blood glucose levels. Urinary phthalate metabolite concentrations were from single spot urine samples collected in 1st and 2nd trimesters. Blood glucose data was abstracted from medical records for non-fasting 50-g glucose challenge tests at 24–28 weeks gestation. Multivariable linear regression models were used to evaluate associations between 7 urinary phthalate metabolites in quartiles and mean glucose adjusted for potential confounders.ResultsEighteen percent of women had glucose levels ≥ 140 mg/dL. Second trimester monoethyl phthalate (MEP) concentrations were positively associated with glucose levels, with adjusted mean (95%CI) glucose levels of 121 mg/dl (114, 128) vs. 109 mg/dL (103, 116) for women in highest and lowest quartiles, respectively. Women in the highest quartile of second trimester mono-isobutyl phthalate (MiBP) concentrations had a mean glucose level 14 mg/dL lower compared to women in the lowest quartile. No other urinary phthalate metabolites were associated with glucose levels.ConclusionsMEP and MiBP—metabolites of diethyl phthalate and dibutyl phthalate, respectively—were associated with higher pregnancy glucose in subfertile women—a population at high risk of glucose intolerance in pregnancy.Electronic supplementary materialThe online version of this article (10.1186/s12940-018-0399-5) contains supplementary material, which is available to authorized users.

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“…Yamauchi et al demonstrated JAK/STAT pathway‐mediated upregulation of 2 REG (Regenerating gene) family genes in 1.1B4 cells following incubation with interleukin‐6 and dexamethasone, implicating polymorphisms or otherwise aberrant expression of these REG genes and/or JAK/STAT factors in the pathology of diabetes. Guven et al examined the effects of monoethyl phthalate on 1.1B4 cells and demonstrated that the compound elicited beta‐cell proliferation and enhanced PDX1 (pancreatic and duodenal homeobox 1) expression in beta‐cells prompting further investigations into the potential effects of environmental phthalates on beta‐cell health. Elumlai et al used the 1.1B4 cell‐line as a model to show that the GTPase Rac1 contributes to glucotoxicity‐induced dysfunction in human beta‐cells through activation of NADPH oxidase, increasing reactive oxygen species and upregulating the expression of cluster determinant 36.…”

Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 99%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

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Low dose monoethyl phthalate (MEP) exposure triggers proliferation by activating PDX-1 at 1.1B4 human pancreatic beta cells

Cited by 18 publications

References 61 publications

Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth

Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth

Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic

Cellular models for beta‐cell function and diabetes gene therapy

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