The Role of Peroxisome Proliferator–Activated Receptor Gamma (PPARγ) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation

Shoaito, Hussein; Petit, Julia; Chissey, Audrey; Auzeil, Nicolas; Gadrey, Jean; Gil, Sophie; Laprévôte, Olivier; Fournier, Thierry; Degrelle, Séverine A.

doi:10.1289/ehp3730

Cited by 63 publications

(42 citation statements)

References 77 publications

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“… 82 Perinatal phthalate exposures lead to perturbation of methyl donor levels and global hypomethylation in rat testis, 83 and administration of the methyl donor choline attenuates the teratogenic effects of phthalate exposure in chick embryos, 84 suggesting that phthalates may interfere with 1-carbon metabolism. Moreover, phthalates have been reported to bind to and modulate the activity of nuclear hormone receptors, including peroxisome proliferator-activated receptors (PPARs), 85 , 86 which function in part through regulation of DNAm. 87 , 88 Studies to determine the sex-specific mechanistic basis for DEHP-induced perturbations in cardiac DNAm are currently underway.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

et al. 2020

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Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

et al. 2020

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“…This study observed that higher levels of MEHP in cord blood were associated with decreased gestational age at delivery. The reason for the conflicting results is that phthalates and their metabolites, such as DEHP and mono-(2-ethylhexyl) phthalate MEHP, can modulate both PPAR [ 157 , 158 ] and prostaglandins [ 153 , 154 ]. PPARs are necessary for maintaining a pregnancy.…”

Section: Phthalates’ Action On Female Reproductive Healthmentioning

confidence: 99%

“…PPARs are necessary for maintaining a pregnancy. DEHP and its metabolites could bind to PPAR and prevent the maternal–fetal communication which allows birth to be initiated [ 157 , 158 ]. Prostaglandins are signaling molecules, which induce contractions of the uterus, leading to birth or abortion.…”

Section: Phthalates’ Action On Female Reproductive Healthmentioning

confidence: 99%

“…Interaction with AR and ER can lead to the impaired action of endogenous signal molecules on hormone-dependent tissue [ 1 , 221 ], such as the endometrium, gonads, breast, adipose tissue, liver, prostate, adrenal gland and skin [ 222 , 223 , 224 ]. Interaction with PPAR can lead to impaired placental function, which is associated with the impaired timing of baby delivery and spontaneous miscarriage occurrence [ 157 , 158 ].…”

Section: Intracellular Signaling Mechanisms Of Phthalates’ Action mentioning

confidence: 99%

“…ER and PPAR are not ligand-specific receptors. The PPAR, ERα, and ERβ ligand-binding domains are significantly larger, allowing for access to diverse groups of small molecules, especially environmental chemicals [ 158 , 234 ]. DEP, DEHP, DiBP, DiNP, DnBP can significantly activate ER [ 229 , 230 , 231 , 235 ], DEHP, DiBP and DnBP can stimulate the activity of PPARs [ 231 , 236 ].…”

Section: Intracellular Signaling Mechanisms Of Phthalates’ Action mentioning

confidence: 99%

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Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

Hlisníková

Petrovičová

Kolena

et al. 2020

IJERPH

147

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The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

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Mono(2-ethylhexyl) phthalate induces transcriptomic changes in placental cells based on concentration, fetal sex, and trophoblast cell type

et al. 2023

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Phthalates are ubiquitous plasticizer chemicals found in consumer products. Exposure to phthalates during pregnancy has been associated with adverse pregnancy and birth outcomes and differences in placental gene expression in human studies. The objective of this research was to evaluate global changes in placental gene expression via RNA sequencing in two placental cell models following exposure to the phthalate metabolite mono(2-ethylhexyl) phthalate (MEHP). HTR-8/SVneo and primary syncytiotrophoblast cells were exposed to three concentrations (1, 90, 180 µM) of MEHP for 24 h with DMSO (0.1%) as a vehicle control. mRNA and lncRNAs were quantified using paired-end RNA sequencing, followed by identification of differentially expressed genes (DEGs), significant KEGG pathways, and enriched transcription factors (TFs). MEHP caused gene expression changes across all concentrations for HTR-8/SVneo and primary syncytiotrophoblast cells. Sex-stratified analysis of primary cells identified different patterns of sensitivity in response to MEHP dose by sex, with male placentas being more responsive to MEHP exposure. Pathway analysis identified 11 KEGG pathways significantly associated with at least one concentration in both cell types. Four ligand-inducible nuclear hormone TFs (PPARG, PPARD, ESR1, AR) were enriched in at least three treatment groups. Overall, we demonstrated that MEHP differentially affects placental gene expression based on concentration, fetal sex, and trophoblast cell type. This study confirms prior studies, as enrichment of nuclear hormone receptor TFs were concordant with previously published mechanisms of phthalate disruption, and generates new hypotheses, as we identified many pathways and genes not previously linked to phthalate exposure.

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The Role of Peroxisome Proliferator–Activated Receptor Gamma (PPARγ) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation

Cited by 63 publications

References 77 publications

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

Mono(2-ethylhexyl) phthalate induces transcriptomic changes in placental cells based on concentration, fetal sex, and trophoblast cell type

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