Mono-(2-ethylhexyl) phthalate induces apoptosis through miR-16 in human first trimester placental cell line HTR-8/SVneo

Meruvu, Sunitha; Zhang, Jian; Bedi, Yudhishtar S.; Choudhury, Mahua

doi:10.1016/j.tiv.2015.11.010

Cited by 52 publications

(36 citation statements)

References 45 publications

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“…In a small pilot study, we estimated that MnBP, MBzP, and MEP were higher, but within an order of magnitude, in urine than in placental tissue by 14-, 28-, and 8-fold respectively. MEHP was 4-fold higher in placental tissue; therefore, we may have slightly underestimated the true exposure to the placenta in this study (J. Adibi and N. Snyder, unpublished data, 2017); this may increase the translational value over previously published studies that dosed with concentrations of MEHP that are 1–3 orders of magnitude higher than urinary levels ( Meruvu et al 2016 ; Tetz et al 2013 ; Wang et al 2016 ).…”

Section: Discussionmentioning

confidence: 68%

An Investigation of the Single and Combined Phthalate Metabolite Effects on Human Chorionic Gonadotropin Expression in Placental Cells

Adibi

Zhao

Zhan

et al. 2017

Environ Health Perspect

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Background:Observational studies have reported associations between maternal phthalate levels and adverse outcomes at birth and in the health of the child. Effects on placental function have been suggested as a biologic basis for these findings.Objective:We evaluated the effects of phthalates on placental function in vitro by measuring relevant candidate genes and proteins.Materials and Methods:Human trophoblast progenitor cells were isolated at 7–14 wk of pregnancy (two female and three male concepti), and villous cytotrophoblast cells (vCTBs) were isolated at 15–20 wk (three female and four male concepti). Cells were cultured in vitro with four phthalate metabolites and their combination at concentrations based on levels found previously in the urine of pregnant women: mono-n-butyl (MnBP, 200 nM), monobenzyl (MBzP, 3μM), mono-2-ethylhexyl (MEHP, 700 nM), and monoethyl (MEP, 1.5μM) phthalates. mRNA levels of CGA, CGB, PPARG, CYP19A1, CYP11A1, PTGS2, EREG, and the intracellular normalβ subunit of human chorionic gonadotropin (hCGβ) and peroxisome proliferator activated receptor normalγ (PPARγ) were measured in the cellular extracts, and protein levels for four forms of secreted hCG were measured in the conditioned media.Results:Previously reported associations between maternal phthalates and placental gene expression were reproduced experimentally: MnBP with CGA, MBzP with CYP11A1, and MEHP with PTGS2. CGB and hCGβ were up-regulated by MBzP. In some cases, there were marked, even opposite, differences in response by sex of the cells. There was evidence of agonism in female cells and antagonism in male cells of PPARγ by simultaneous exposure to multiple phthalates.Conclusions:Concentrations of MnBP, MBzP and MEHP similar to those found in the urine of pregnant women consistently altered hCG and PPARγ expression in primary placental cells. These findings provide evidence for the molecular basis by which phthalates may alter placental function, and they provide a preliminary mechanistic hypothesis for opposite responses by sex. https://doi.org/10.1289/EHP1539

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Section: Discussionmentioning

confidence: 68%

An Investigation of the Single and Combined Phthalate Metabolite Effects on Human Chorionic Gonadotropin Expression in Placental Cells

Adibi

Zhao

Zhan

et al. 2017

Environ Health Perspect

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“…A study in mice showed that BPA affected placental loss-of-imprinting and decreased both global and CpG-specific DNA methylation [ 53 ], while also in mice, DEHP was shown to increase maternal bias (via imprinting) of the Rasgrf1 gene [ 54 ]. An in vitro study in 2 placental cell lines (HTR-8/Svneo and 3A) showed that BPA treatment affected 25 and 60 (respectively) miRs [ 55 ], while two studies in HTR-8/Svneo cells showed that treatment with MEHP (the primary oxidative metabolite of DEHP) increased the expression of numerous miRs, including miR-16, which was shown to mediate MEHP-induced decrease in the BCL-2/BAX ratio, a measure of cellular apoptosis [ 56 , 57 ]. Given the findings from these mechanistic studies, and the established role of epigenetics in placental and fetal development, researchers have begun the arduous task of assessing associations between BPA/phthalate exposure and placental epigenetic disruption in humans.…”

Section: Introductionmentioning

confidence: 99%

Impacts of bisphenol A (BPA) and phthalate exposures on epigenetic outcomes in the human placenta

Strakovsky

Schantz

2018

Environmental Epigenetics

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The placenta guides fetal growth and development. Bisphenol A (BPA) and phthalates are widespread environmental contaminants and endocrine disruptors, and the placental epigenetic response to these chemicals is an area of growing research interest. Therefore, our objective was to summarize research linking BPA or phthalate exposure to placental outcomes in human pregnancies, with a particular focus on epigenetic endpoints. In PubMed, studies were selected for review (without limiting start date and ending on 1 May 2018) if they reported any direct effects of BPA or phthalates on the placenta in humans. Collectively, available studies suggest that BPA and phthalate exposures are associated with changes to placental micro-RNA expression, DNA methylation, and genomic imprinting. Furthermore, several studies suggest that fetal sex may be an important modifier of placental outcomes in response to these chemicals. Studies in humans demonstrate associations of BPA and phthalate exposure with adverse placental outcomes. Moving forward, more studies should consider sex differences (termed “placental sex”) in the measured outcomes, and should utilize appropriate statistical approaches to assess modification by fetal sex. Furthermore, more consistent sample collection and molecular outcome assessment paradigms will be indispensable for making progress in the field. These advances, together with improved non-invasive tools for measuring placental function and outcomes across pregnancy, will be critical for understanding the mechanisms driving placental epigenetic disruption in response to BPA and phthalates, and how these disruptions translate into placental and fetal health.

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“…Exposure to MEHP increased miR-16 expression in a time- and dose- dependent manner, while inducing apoptosis. The results showed that miR-16 could be induced after only four hours of exposure, and was significantly upregulated with increasing concentrations of MEHP [ 92 ]. miR-16 has been shown to regulate cell cycle genes, including cyclin D1 ( CCND1 ), cyclin E1 ( CCNE1 ), and CDK1 , to induce G 0 /G 1 arrest; it has also been implicated in playing a role in tumor growth [ [93] , [94] , [95] ].…”

Section: Environmental Toxicantsmentioning

confidence: 99%

Placental microRNAs: Responders to environmental chemicals and mediators of pathophysiology of the human placenta

et al. 2020

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Mono-(2-ethylhexyl) phthalate induces apoptosis through miR-16 in human first trimester placental cell line HTR-8/SVneo

Cited by 52 publications

References 45 publications

An Investigation of the Single and Combined Phthalate Metabolite Effects on Human Chorionic Gonadotropin Expression in Placental Cells

An Investigation of the Single and Combined Phthalate Metabolite Effects on Human Chorionic Gonadotropin Expression in Placental Cells

Impacts of bisphenol A (BPA) and phthalate exposures on epigenetic outcomes in the human placenta

Placental microRNAs: Responders to environmental chemicals and mediators of pathophysiology of the human placenta

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