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Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling.

ABSTRACT: Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

SUBMITTER: Sant KE

PROVIDER: S-EPMC7429360 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Embryonic exposure to Mono(2-ethylhexyl) phthalate (MEHP) disrupts pancreatic organogenesis in zebrafish (Danio rerio).

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.

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Thyroid endocrine disruption in zebrafish larvae after exposure to mono-(2-ethylhexyl) phthalate (MEHP).

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Mono-2-ethylhexyl phthalate disrupts neurulation and modifies the embryonic redox environment and gene expression.

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Mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) but not di(2-ethylhexyl) phthalate (DEHP) bind productively to the peroxisome proliferator-activated receptor ?.

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Project description:Di-2-ethylhexyl phthalate (DEHP) is an environmental contaminant commonly used as a plasticizer in polyvinyl chloride products. Exposure to DEHP has been linked to adverse pregnancy outcomes in humans including preterm birth, low birth-weight, and pregnancy loss. Although oxidative stress is linked to the pathology of adverse pregnancy outcomes, effects of DEHP metabolites, including the active metabolite, mono-2-ethylhexyl phthalate (MEHP), on oxidative stress responses in placental cells have not been previously evaluated. The objective of the current study is to identify MEHP-stimulated oxidative stress responses in human placental cells. We treated a human placental cell line, HTR-8/SVneo, with MEHP and then measured reactive oxygen species (ROS) generation using the dichlorofluorescein assay, oxidized thymine with mass-spectrometry, redox-sensitive gene expression with qRT-PCR, and apoptosis using a luminescence assay for caspase 3/7 activity. Treatment of HTR-8 cells with 180μM MEHP increased ROS generation, oxidative DNA damage, and caspase 3/7 activity, and resulted in differential expression of redox-sensitive genes. Notably, 90 and 180μM MEHP significantly induced mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2), an enzyme important for synthesis of prostaglandins implicated in initiation of labor. The results from the present study are the first to demonstrate that MEHP stimulates oxidative stress responses in placental cells. Furthermore, the MEHP concentrations used were within an order of magnitude of the highest concentrations measured previously in human umbilical cord or maternal serum. The findings from the current study warrant future mechanistic studies of oxidative stress, apoptosis, and prostaglandins as molecular mediators of DEHP/MEHP-associated adverse pregnancy outcomes.

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Mono-(2-ethylhexyl) phthalate Promotes Dengue Virus Infection by Decreasing IL-23-Mediated Antiviral Responses.

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| S-EPMC7919524 | biostudies-literature

Impact of mono(2-ethylhexyl) phthalate (MEHP) on the development of mouse embryo in vitro.

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Transcription profiling of rat testes following exposure to mono-(2-ethylhexyl) phthalate

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

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