Mono(2-ethylhexyl) phthalate (MEHP) induces transcriptomic alterations in oocytes and their derived blastocysts

Kalo, Dorit; Carvalho, Anais Vitorino; Archilla, Catherine; Duranthon, Véronique; Moroldo, Marco; Levin, Yishai; Kupervaser, Meital; Smith, Yoav; Roth, Zvi

doi:10.1016/j.tox.2019.04.016

Cited by 31 publications

(24 citation statements)

References 80 publications

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“…Culturing of bovine COCs with 50 µM MEHP increased the proportion of apoptotic oocytes (TUNEL+) ( Kalo and Roth, 2015 ) and was associated with alteration in the expression of ASAH1 gene encodes the acid ceramidase enzyme, an antiapoptotic factor ( Grossman et al., 2012 ). In-depth transcript screening and proteomic analysis strongly support the oocyte transcripts' sensitivity to MEHP, since alterations in several genes associated with mitochondria and the apoptotic cascade have been reported ( Kalo et al., 2019 ). In support of this, MEHP induced alterations in the expression of genes associated with mitochondrial function in bovine COCs (cytochrome bc1 complex; CYC1 , Mitochondrially Encoded Cytochrome C Oxidase I ; MT-CO1 and ATP synthase subunit beta; ATP5B ), mouse fetal oocytes (superoxide dismutase 1 ; Sod1 and NADH dehydrogenase 1; Nd1 ) and porcine COCs ( SOD1 and Catalase; CAT ) ( Kalo and Roth, 2015 ; Bonilla and del Mazo, 2010 ; Zhang et al., 2018 ).…”

Section: Effects Of Dehp and Mehp On The Oocytementioning

confidence: 95%

“…An accurate cAMP level is required for chromatin transition, and synchronization between nuclear and cytoplasmic maturation (Gilchrist et al, 2011;Luciano et al, 2011). Microarray analysis of MEHP-treated bovine oocytes revealed alterations in seven transcripts associated with the cAMP-signaling pathway (Kalo et al, 2019). In rats, MEHP inhibited the accumulation of cAMP in Sertoli cells (Heindel and Chapin, 1989).…”

Section: Effects Of Dehp and Mehp On The Oocytementioning

confidence: 99%

“…MEHP-induced impairment in POU5F1 and SOX2 transcript abundance which associated with pluripotency, was found in blastocysts developed from oocytes exposed to relatively low MEHP concentrations (Kalo and Roth, 2017), suggesting that these embryos are of inferior quality. In-vitro maturation of bovine oocytes with 20 nM MEHP induced a carryover effect on the transcriptomic profile of the developing embryo, expressed by the altered expression of 260 genes (Kalo et al, 2019). Direct exposure of mouse embryos to 100-1000 μg/mL MEHP (corresponding to 0.4-3.6 mM) impaired the expression of metabolic genes, in particular those related to the electron transport chain (Sant et al, 2016).…”

Section: Carryover Effect Of Dehp and Mehp From The Oocyte To The Embryomentioning

confidence: 99%

“…In-vitro maturation of oocytes in follicular fluid aspirated from DEHP-treated cows (i.e., containing 20 nM MEHP) reduced cleavage and blastocyst-formation rates ( Kalo et al., 2015 ). Blastocysts developed from MEHP-treated oocytes showed different expression patterns of genes involved in intracellular mechanisms such as pluripotency, apoptosis, and placental development ( Kalo et al., 2019 ). Culturing of bovine oocytes with 50 µM MEHP altered the levels of POU5F1 in 2-cell-stage embryos ( Grossman et al., 2012 ).…”

Section: Carryover Effect Of Dehp and Mehp From The Oocyte To The Embmentioning

confidence: 99%

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Effect of environmental contamination on female and male gametes – A lesson from bovines

2020

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Endocrine-disrupting compounds (EDCs) and foodborne contaminants are environmental pollutants that are considered reproductive toxicants due to their deleterious effects on female and male gametes. Among the EDCs, the phthalate plasticizers are of growing concern. In-vivo and in-vitro models indicate that the oocyte is highly sensitive to phthalates. This review summarizes the effects of di(2-ethylhexyl) phthalate and its major metabolite mono(2-ethyhexyl) phthalate (MEHP) on the oocyte. MEHP reduces the proportion of oocytes that fertilize, cleave and develop to the blastocyst stage. This is associated with negative effects on meiotic progression, and disruption of cortical granules, endoplasmic reticulum and mitochondrial reorganization. MEHP alters mitochondrial membrane polarity, increases reactive oxygen species levels and induces alterations in genes associated with oxidative phosphorylation. A carryover effect from the oocyte to the blastocyst is manifested by alterations in the transcriptomic profile of blastocysts developed from MEHP-treated oocytes. Among foodborne contaminants, the pesticide atrazine (ATZ) and the mycotoxin aflatoxin B1 (AFB1) are of high concern. The potential hazards associated with exposure of spermatozoa to these contaminants and their carryover effect to the blastocyst are described. AFB1 and ATZ reduce spermatozoa's viability, as reflected by a high proportion of cells with damaged plasma membrane; induce acrosome reaction, expressed as damage to the acrosomal membrane; and interfere with mitochondrial function, characterized by hyperpolarization of the membrane. ATZ and AFB1-treated spermatozoa show a high proportion of cells with fragmented DNA. Exposure of spermatozoa to AFB1 and ATZ reduces fertilization and cleavage rates, but not that of blastocyst formation. However, fertilization with AFB1-or ATZ-treated spermatozoa impairs transcript expression in the formed blastocysts, implying a carryover effect. Taken together, the review indicates the risk of exposing farm animals to environmental contaminants, and their deleterious effects on female and male gametes and the developing embryo.

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Section: Effects Of Dehp and Mehp On The Oocytementioning

confidence: 95%

Section: Effects Of Dehp and Mehp On The Oocytementioning

confidence: 99%

Section: Carryover Effect Of Dehp and Mehp From The Oocyte To The Embryomentioning

confidence: 99%

Section: Carryover Effect Of Dehp and Mehp From The Oocyte To The Embmentioning

confidence: 99%

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Effect of environmental contamination on female and male gametes – A lesson from bovines

2020

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“…COCs matured in medium supplemented with follicular fluid aspirated from the ovaries of these exposed cows had lower numbers of oocytes reaching the MII stage, lower numbers of 2-to 4-cell embryos, and a trend toward lower numbers of 7-day blastocysts (91). The concentration of MEHP found in follicular fluid was then used to design an in vitro study of transcriptomic and proteomic changes in bovine blastocysts after the COCs were exposed to 20-nM MEHP over 22 hours before fertilization (92). Exposure to MEHP at this level did not alter the percentage of COCs reaching 2-and 4-cell-stage embryos or blastocyst formation.…”

Section: Acute Exposure Of Gametes To Plasticizers In Vitromentioning

confidence: 99%

Phthalates in albumin from human serum: implications for assisted reproductive technology

et al. 2021

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Albumin, a vital protein in cell culture systems, is derived from whole blood or blood products. The culture of human gametes and developing embryos for assisted reproductive technology (ART) uses albumin of human origin. Human serum albumin (HSA) is derived from expired blood obtained from blood banks. This blood has been stored in polyvinyl chloride bags made clear and flexible with di-2ethylhexyl phthalate (DEHP). However, DEHP can leach from the bags into stored blood and cofractionate with HSA during albumin isolation. DEHP and its metabolite, mono-ethylhexyl phthalate, are known endocrine disruptors that are reported to have negative effects when directly supplemented in media for in vitro fertilization using gametes from a variety of animals. Therefore, the contamination of ART media with DEHP and mono-ethylhexyl phthalate through HSA supplementation may affect the outcomes of ART procedures. Although the embryology laboratory is strictly monitored to prevent a wide variety of contaminations, phthalate contamination of HSA has not been broadly examined. This review outlines the function of HSA in ART procedures and the production of HSA from whole blood. Finally, the review highlights the effects of acute phthalate exposures on gametes during in vitro procedures. Phthalates found in human serum albumin are present in media used for ART at levels that impair developmental endpoints in model species.

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Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

2020

J of Applied Toxicology

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Mono (2‐ethylhexyl) phthalate (MEHP) is a major metabolite of di (2‐ethylhexyl) phthalate (DEHP). This study aimed to observe the toxic effect of MEHP on human endometrial microvascular endothelial cells (HEMECs) and its potential molecular mechanism. HEMECs were exposed to different concentrations of MEHP (0, 50, 100, and 200 nM). Cell viability and apoptosis were assessed by cell counting kit‐8 (CCK‐8) and flow cytometry assays. Western blot was performed to examine the expression of apoptosis‐related proteins (Bcl‐2, Bax, and Caspase‐3). Moreover, the expression of pyroptosis‐related Caspase‐1 was detected by western blot and immunofluorescence assays. Lactate dehydrogenase (LDH) release levels were evaluated in HEMECs treated with MEHP and/or Caspase‐1 inhibitor Ac‐YVAD‐CHO. After exposure to MEHP, NLRP3 expression was examined by reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot. LDH release and apoptosis levels were tested in HEMECs induced by MEHP and/or siNLRP3. MEHP significantly induced cell viability and inhibited apoptosis for HEMECs, with a concentration‐dependent manner. Furthermore, Bcl‐2/Bax ratio was distinctly reduced and Caspase‐3 expression was increased in HEMECs after exposure to MEHP. Western blot and immunofluorescence results confirmed that MEHP markedly augmented Caspase‐1 expression in HEMECs. Furthermore, LDH release levels were fortified in HEMECs treated with MEHP, which were improved following cotreatment with Ac‐YVAD‐CHO. At the mRNA and protein levels, NLRP3 expression was prominently increased in HEMECs exposed to MEHP. NLRP3 knockdown markedly ameliorated the increase in LDH release and apoptosis induced by MEHP exposure in HEMECs. Our findings suggested that exposure to MEHP facilitates apoptosis and pyroptosis of HEMECs through NLRP3 inflammasome.

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Mono(2-ethylhexyl) phthalate (MEHP) induces transcriptomic alterations in oocytes and their derived blastocysts

Cited by 31 publications

References 80 publications

Effect of environmental contamination on female and male gametes – A lesson from bovines

Effect of environmental contamination on female and male gametes – A lesson from bovines

Phthalates in albumin from human serum: implications for assisted reproductive technology

Exposure to mono (2‐ethylhexyl) phthalate facilitates apoptosis and pyroptosis of human endometrial microvascular endothelial cells through NLRP3 inflammasome

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