Testis Transcriptome Profiles of Peripubertal and Adult Rodents exposed to an Acute dose of MEHP(Mono(2-ethylhexyl) phthalate)
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ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus
PROVIDER: GSE229734 | GEO | 2023/12/13
REPOSITORIES: GEO
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Project description:Mono(2-ethylhexyl) phthalate (MEHP), the main di(2-ethylhexyl) phthalate (DEHP) metabolite, is a known reproductive toxicant. Residual levels of 20 nM MEHP have been found in follicular fluid aspirated from IVF-treated women and DEHP-treated animals. It is not yet clear whether these residual MEHP levels have any effect on the follicle-enclosed oocyte or developing embryo. To clarify this point, bovine oocytes were matured with or without 20 nM MEHP for 22 h. Microarray analysis was performed for both mature oocytes and 7-day blastocysts. A feasibility examination was performed on mature oocytes (n = 200/group) to reveal a possible direct effect on the oocyte proteomic profile. Transcriptome analysis revealed MEHP-induced alterations in the expression of 456 and 290 genes in oocytes and blastocysts, respectively. The differentially expressed genes are known to be involved in various biological pathways, such as transcription process, cytoskeleton regulation and metabolic pathway. Among these, the expression of 9 genes was impaired in both oocytes exposed to MEHP (i.e., direct effect) and blastocysts developed from those oocytes (i.e., carryover effect). In addition, 191 proteins were found to be affected by MEHP in mature oocytes. The study explores, for the first time, the risk associated with exposing oocytes to physiologically relevant MEHP concentrations to the maternal transcripts. Although it was the oocytes that were exposed to MEHP, alterations carried over to the blastocyst stage, following embryonic genome activation, implying that these embryos are of low quality.
2019-05-09 | PXD012092 | Pride
Project description:Testis Transcriptome Profiles of Peripubertal and Adult Rodents exposed to an Acute dose of MEHP(Mono(2-ethylhexyl) phthalate)
| PRJNA955727 | ENA
Project description:RATIONALE:The most frequently occurring phthalate, di(2-ethylhexyl) phthalate (DEHP), causes adverse effects on glucose homeostasis and insulin sensitivity in several cell models and epidemiological studies. However, thus far, there is no information available on the molecular interaction of phthalates and one of the key regulators of the metabolism, the peroxisome proliferator-activated receptor gamma (PPAR?). Since the endogenous ligand of PPAR?, 15-deoxy-delta-12,14-prostaglandin J2 (15?-PGJ2 ), features structural similarity to DEHP and its main metabolites produced in human hepatic metabolism, mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), we tested the hypothesis of direct interactions between PPAR? and DEHP or its transformation products. METHODS:Hydrogen/deuterium exchange mass spectrometry (HDX-MS) and docking were conducted to obtain structural insights into the interactions and surface plasmon resonance (SPR) analysis to reveal information about binding levels. To confirm the activation of PPAR? upon ligand binding on the cellular level, the GeneBLAzer® bioassay was performed. RESULTS:HDX-MS and SPR analyses demonstrated that the metabolites MEHP and MEOHP, but not DEHP itself, bind to the ligand binding pocket of PPAR?. This binding leads to typical activation-associated conformational changes, as observed with its endogenous ligand 15?-PGJ2 . Furthermore, the reporter gene assay confirmed productive interaction. DEHP was inactive up to a concentration of 14??M, while the metabolites MEHP and MEOHP were active at low micromolar concentrations. CONCLUSIONS:In summary, this study gives structural insights into the direct interaction of PPAR? with MEHP and MEOHP and shows that the DEHP transformation products may modulate the lipid metabolism through PPAR? pathways.
| S-EPMC6367069 | biostudies-literature
Project description:Phthalates are extensively used as plasticizers in a variety of daily-life products, resulting in widespread distribution in aquatic environments. However, limited information is available on the endocrine disrupting effects of phthalates in aquatic organisms. The aim of the present study was to examine whether exposure to mono-(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di-(2-ethylhexyl) phthalate (DEHP) disrupts thyroid endocrine system in fish. In this study, zebrafish (Danio rerio) embryos were exposed to different concentrations of MEHP (1.6, 8, 40, and 200 μg/L) from 2 h post-fertilization (hpf) to 168 hpf. The whole-body content of thyroid hormone and transcription of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis were examined. Treatment with MEHP significantly decreased whole-body T4 contents and increased whole-body T3 contents, indicating thyroid endocrine disruption. The upregulation of genes related to thyroid hormone metabolism (Dio2 and UGT1ab) might be responsible for decreased T4 contents. Elevated gene transcription of Dio1 was also observed in this study, which might assist to degrade increased T3 contents. Exposure to MEHP also significantly induced transcription of genes involved in thyroid development (Nkx2.1 and Pax8) and thyroid hormone synthesis (TSHβ, NIS and TG). However, the genes encoding proteins involved in TH transport (transthyretin, TTR) was transcriptionally significantly down-regulated after exposure to MEHP. Overall, these results demonstrate that acute exposure to MEHP alters whole-body contents of thyroid hormones in zebrafish embryos/larvae and changes the transcription of genes involved in the HPT axis, thus exerting thyroid endocrine toxicity.
| S-EPMC3962405 | biostudies-literature
Project description:In rodent models, phthalate exposure alters both the fetal and pubertal testis, but the resulting histopathological changes are divergent. This suggests that the underlying molecular and cellular phthalate mechanism may be age-dependent. Using genome-wide expression profiling of acutely-exposed rats, the initial molecular response in pubertal rat testis following in vivo phthalate exposure was determined. For this study, postnatal day 28 rats were exposed to a single dose of 1 g/kg mono-(2-ethyl)hexyl phthalate (MEHP) and assayed at 1, 2, 3, 6, and 12 hrs thereafter using Affymetrix Rat Genome 230 2.0 Arrays. Experiment Overall Design: At each timepoint, testes from 3 treated and 3 control (corn oil gavage) were analzyed.
2007-11-06 | E-GEOD-4514 | biostudies-arrayexpress
Project description:Many commercial and household products such as lubricants, cosmetics, plastics, and paint contain phthalates, in particular bis-(2-ethyhexyl)-phthalate (DEHP). As a consequence, phthalates have been found in a number of locations and foods (streambeds, household dust, bottled water and dairy products). Epidemiological and animal studies analysing phthalate exposure in males provide evidence of degradation in sperm quality, associated to an increase in the incidence of genital birth defects and testicular cancers. In the testis, spermatogenesis is maintained throughout life by a small number of spermatogonial stem cells (SSCs) that self-renew or differentiate to produce adequate numbers of spermatozoa. Disruption or alteration of SSC self-renewal induce decreased sperm count and sperm quality, or may potentially lead to testicular cancer. GDNF, or glial cell-line-derived neurotrophic factor, is a growth factor that is essential for the self-renewal of SSCs and continuous spermatogenesis. In the present study, the SSC-derived cell line C18-4 was used as a model for preliminary assessment of the effects of mono-(2-ethylhexyl)-phthalate (MEHP, main metabolite of DEHP) on spermatogonial stem cells. Our data demonstrate that MEHP disrupts one of the known GDNF signalling pathways in these cells. MEHP induced a decrease of C18-4 cell viability in a time- and dose-dependent manner, as well as a disruption of ERK1/2 activation but not of SRC signalling. As a result, we observed a decrease of expression of the transcription factor FOS, which is downstream of the GDNF/ERK1/2 axis in these cells. Taken together, our data suggest that MEHP exposure affects SSC proliferation through inhibition of specific signalling molecules.
| S-EPMC3377775 | biostudies-literature
Project description:Mono(2-ethylhexyl) phthalate (MEHP) is the bioactive metabolite of di(2-ethylhexyl) phthalate, a plasticizing agent and persistent environmental contaminant associated with obesity, developmental abnormalities, and oxidative stress. Nrf2 (Nfe2l2) is a transcription factor that regulates cytoprotective genes as part of the adaptive antioxidant response. We previously identified the pancreas as a sensitive target of oxidative stress during embryonic development. The goals of this study were to 1) characterize the effects of MEHP exposure on pancreatic development, and 2) determine whether oxidative stress contributes to MEHP embryotoxicity. Zebrafish (Danio rerio) embryos from AB wildtype and Tg(ins:GFP;nrf2afh318/fh318) were exposed to 0 or 200 μg/L MEHP at 3 h post fertilization (hpf) through 168 hpf to assess pancreatic organogenesis. MEHP exposure significantly decreased β-cell area at all timepoints (48, 72, 96, 168 hpf), but Nrf2a did not significantly protect against islet hypomorphism. Tg(gcga:GFP) embryos exposed to MEHP showed a decrease in α-cell area in the islet across the same timepoints. Tg(ptf1a:GFP) embryos were assessed at 80 and 168 hpf for exocrine pancreas length. MEHP exposure decreased growth of the exocrine pancreas. Expression of pancreas genes insa, sst2 and ptf1a was significantly reduced by MEHP exposure compared to controls. Glutathione (GSH) concentrations and redox potentials were quantified at 72 hpf by HPLC, but no significant changes were observed. However, expression of the GSH-related genes gstp1 and gsr were significantly altered by MEHP exposure. These data indicate that the developing pancreas is a sensitive target tissue of embryonic exposure to MEHP.
| S-EPMC5788038 | biostudies-literature
Project description:Mono(2-ethylhexyl) phthalate (MEHP) is the most studied metabolite of di(2-ethylhexyl) phthalate (DEHP), a phthalate found in cosmetics, flooring, paints, and plastics products, including toys and medical tubing. Humans are frequently exposed to this compound due to its ubiquitous presence in our environment. DEHP and MEHP are known to be endocrine-disrupting chemicals and exposure levels have been associated to decreased reproductive success. However, few studies have focused on the direct effects of MEHP on embryos. The present study investigated effects of MEHP (0.1, 1, 10, 100 and 1000 µM) on mice preimplantation embryonic development, evaluating percentage of blastocyst formation, hatching from zona pellucida, methylation-related genes, cell lineage commitment, micronucleation, and adherens junction marker at different stages of development during in vitro culture for 6 days. We show MEHP negatively impacts embryo competence by reducing blastocyst formation and hatching at 100 and 1000 µM. In addition, 100 µM MEHP increases the expression of Tet3 gene in blastocysts, which is related to a reduction of DNA methylation, an important mechanism regulating gene expression. Exposed embryos that completed the hatching process in groups 0.1, 1 and 10 µM MEHP had similar number of inner cell mass and trophectoderm cells compared to the control, while micronucleation occurrence and E-cadherin expression was not affected in exposed morulae by MEHP at 10 or 100 µM. Our results showed that high concentrations of MEHP can negatively impact embryo development. New studies unveiling the mechanism of toxicity involved and encompassing further developmental stages are warranted for further understanding.
| S-EPMC10195034 | biostudies-literature
Project description:Histiotrophic nutrition pathways (HNPs) are processes by which the organogenesis-stage conceptus obtains nutrients, amino acids, vitamins and cofactors required for protein biosynthesis and metabolic activities. Nutrients are captured from the maternal milieu as whole proteins and cargoes via receptor-mediated endocytosis in the visceral yolk sac (VYS), degraded by lysosomal proteolysis and delivered to the developing embryo (EMB). Several nutrients obtained by HNPs are required substrates for one-carbon (C1) metabolism and supply methyl groups required for epigenetic processes, including DNA and histone methylation. Increased availability of methyl donors has been associated with reduced risk for neural tube defects (NTDs). Here, we show that mono-2-ethylhexyl phthalate (MEHP) treatment (100 or 250μM) alters HNPs, C1 metabolism and epigenetic programming in the organogenesis-stage conceptus. Specifically, 3-h MEHP treatment of mouse EMBs in whole culture resulted in dose-dependent reduction of HNP activity in the conceptus. To observe nutrient consequences of decreased HNP function, C1 components and substrates and epigenetic outcomes were quantified at 24h. Treatment with 100-μM MEHP resulted in decreased dietary methyl donor concentrations, while treatment with 100- or 250-μM MEHP resulted in dose-dependent elevated C1 products and substrates. In MEHP-treated EMBs with NTDs, H3K4 methylation was significantly increased, while no effects were seen in treated VYS. DNA methylation was reduced in MEHP-treated EMB with and without NTDs. This research suggests that environmental toxicants such as MEHP decrease embryonic nutrition in a time-dependent manner and that epigenetic consequences of HNP disruption may be exacerbated in EMB with NTDs.
| S-EPMC4750404 | biostudies-literature
Project description:We report the results of an RNA-seq analysis conducted as part of an experiment investigating the effects of the phthalate, mono-(2-ethylhexyl) phthalate (MEHP), and all-trans retinoic acid (ATRA) on cultured fetal mouse testes. The goal of the study was to determine whether fetal testis toxicity of MEHP is partially driven by disruption of retinoic acid signaling.
2022-02-05 | GSE195969 | GEO