Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actions

Kumar, Narender; Sharan, Shruti; Srivastava, Swati; Roy, Partha

doi:10.1016/j.reprotox.2014.06.008

Cited by 43 publications

(34 citation statements)

References 46 publications

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“…[43, 44] Another study suggests that MEP has estrogenic activity. [51] As such, it is possible that MEP could alter GWG or impaired glucose tolerance through hormonal pathways, but these exact mechanisms need to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors

James‐Todd

Meeker

Huang

et al. 2016

Environment International

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Background Epidemiologic studies suggest phthalate metabolite concentrations are associated with type 2 diabetes. GDM is a strong risk factor for type 2 diabetes. Little is known about phthalates and GDM risk factors (i.e. 1st trimester body mass index (BMI), gestational weight gain (GWG), and 2nd trimester glucose levels). Methods A total of 350 women participating in Lifecodes pregnancy cohort (Boston, MA), delivered at term and had pregnancy urinary phthalate metabolite concentrations. Nine specific gravity-adjusted urinary phthalate metabolites were evaluated. General linear regression was used to assess associations between quartiles of phthalate metabolites and continuous 1st trimester BMI and late 2nd trimester blood glucose. Linear mixed models were used for total GWG. Multivariable logistic regression was used for phthalate concentrations and categorized GWG and impaired glucose tolerance defined as glucose ≥ 140mg/dL based on a 50-gram glucose load test. Models were adjusted for potential confounders. Results There were no associations between 1st trimester urinary phthalate metabolite concentrations and 1st trimester BMI. Mono-ethyl phthalate (MEP) concentrations averaged across pregnancy were associated with a 2.17 increased odds of excessive GWG (95% CI: 0.98, 4.79). Second trimester MEP was associated with an increased odds of impaired glucose tolerance (adj. OR: 7.18; 95% CI: 1.97, 26.15). Di-2-ethylhexyl phthalate metabolite concentrations were inversely associated with impaired glucose tolerance (adj. OR: 0.25; adj. 95% CI: 0.08, 0.85). Conclusions Higher exposure to di-ethyl phthalate, the parent compound of MEP, may be associated with excessive GWG and impaired glucose tolerance; higher di-2-ethylhexyl phthalate was associated with reduced odds of impaired glucose tolerance.

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Section: Discussionmentioning

confidence: 99%

Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors

James‐Todd

Meeker

Huang

et al. 2016

Environment International

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“…Endocrine disruptors were first identified as compounds with estrogenic potential [42] and, as such, act via the estrogen/androgen receptor pathway [43, 44]. Indeed, the estrogen receptor is involved also in stimulation of proliferation and transcription in pituitary cell lines [14, 36, 39, 45], mainly via the ERK pathway [16].…”

Section: Discussionmentioning

confidence: 99%

Benzene and 2-ethyl-phthalate induce proliferation in normal rat pituitary cells

et al. 2016

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PurposeEndocrine disruptors are known to modulate a variety of endocrine functions and increase the risk for neoplasia. Epidemiological data reported increased prevalence of pituitary tumors in high industrial areas while genotyping studies showed that mutations in the aryl hydrocarbon receptor (AhR) interacting protein (AIP)—chaperone to the dioxin ligand AhR—gene are linked to predisposition to pituitary tumor development. Aim of the present study was to establish whether endocrine pollutants can induce cell proliferation in normal rat pituitary cells.MethodsPituitary primary cultures were incubated with 250, 650 and 1250 pM benzene or 2-ethyl-phthalate for up to 96 h and viability, energy content and cell proliferation assessed. Expression of pituitary tumor transforming gene (PTTG), cyclin D1 (Ccnd1), AhR and AIP was quantified by RT-qPCR.ResultsIncubation with benzene or 2-ethyl-phthalate increased viability and energy content in pituitary cells. The endocrine disruptors also increased cell proliferation as well as Ccnd1 and PTTG expression. Increased AhR and AIP expression was observed after incubation with the two pollutants.ConclusionsOur findings indicate that benzene and 2-ethyl-phthalate activate AhR/AIP expression and stimulate proliferation in normal rat pituitary cells. This study is the first demonstration that pollutants can induce normal pituitary cells to proliferate and provides a link between epidemiological and genomic findings in pituitary tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s11102-016-0777-3) contains supplementary material, which is available to authorized users.

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“…In secondary analyses, we examined effect measure modification by body mass index (BMI) (

) and BC subtype as defined by estrogen receptor (ER) status (

and

). We hypothesized that higher phthalate metabolite concentrations, in particular those from phthalates which display estrogenic activity in vitro or in animal studies [e.g., MEP, metabolite of DEP ( Kumar et al 2014 ); and MBzP, metabolite of benzyl butyl phthalate (BBP) ( Chen et al 2014 ; Kang and Lee 2005 )], would be positively associated with BC and subsequent BC-specific mortality. By contrast, we hypothesized that metabolites of antiandrogenic phthalates [e.g., mono-isobutyl phthalate (MiBP) and MCPP, metabolites of di-isobutyl phthalate (DiBP) and of several HMWPs (e.g., MCPP)], and the DEHP metabolites MEHP, mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), MECPP ( Borch et al 2006 ), and monocarboxyoctyl phthalate (MCOP), metabolite of di-isononyl phthalate ( Howdeshell et al 2008 ; Lee and Koo 2007 ), would be inversely associated with BC and subsequent BC-specific mortality.…”

Section: Introductionmentioning

confidence: 99%

Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project

Parada

Gammon

Chen

et al. 2018

Environ Health Perspect

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Background:Phthalates, known endocrine disruptors, may play a role in breast carcinogenesis. Few studies have examined phthalates in relation to breast cancer (BC), and, to our knowledge, none have considered survival following BC.Objectives:We examined 11 urinary phthalate metabolites, individually and as molar sum groupings, in association with BC incidence and subsequent survival.Methods:Our study includes 710 women diagnosed with first primary BC in 1996–1997 and 598 women without BC from Long Island, New York. Within 3 mo of diagnosis, participants provided spot urine samples. Nine phthalate metabolites were measured in all women; two [monocarboxyoctyl phthalate (MCOP) and monocarboxy-isononyl phthalate (MCNP)] were measured in 320 women with and 205 without BC. Women with BC were followed since diagnosis using the National Death Index; during follow-up (median=17.6y), we identified 271 deaths (98 BC related). We examined creatinine-corrected metabolite concentrations in association with: BC, using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and all-cause/BC-specific mortality, using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We also examined effect modification by body mass index (BMI) and estrogen receptor (ER) status.Results:The highest (vs. lowest) quintiles of mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), MCNP, and MCOP were associated with BC ORs ranging from 0.71–0.73. The highest (vs. lowest) quintiles of mono(2-ethylhexyl) phthalate (MEHP) and MCOP were associated with BC-specific mortality HRs of 0.54 (95% CI: 0.28, 1.04) and 0.55 (95% CI: 0.23, 1.35), respectively. For BC-specific mortality, interactions were significant between BMI and mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), with positive associations among women with BMI<25 and inverse associations among women with BMI≥25.0 kg/m2.Conclusions:Consistent with laboratory evidence, we observed inverse associations between urinary concentrations of several phthalate metabolites and BC and subsequent survival; however, these results should be interpreted with caution given that biospecimen collection among women with BC occurred after diagnosis, which may be of particular concern for our case–control findings. https://doi.org/10.1289/EHP2083

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Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actions

Cited by 43 publications

References 46 publications

Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors

Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors

Benzene and 2-ethyl-phthalate induce proliferation in normal rat pituitary cells

Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project

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