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Diethylhexyl phthalate induces teratogenic effects through oxidative stress response in a chick embryo model.

ABSTRACT: Diethylhexyl phthalate (DEHP) is known as a persistent environmental pollutant. However, the possible effects of DEHP on human neural tube defects (NTDs) remain elusive. We set out to investigate the exposure of DEHP in human and explore the association of DEHP and NTDs. The level of DEHP in maternal urine was measured and analyzed by GC-MS. To further validate the results in human NTDs, chick embryos were used as animal models. Viability, reactive oxygen species (ROS) level, oxidative stress indicators and apoptosis were detected in DEHP-treated chick embryos. Our research revealed that the detection ratio of positive DEHP and its metabolites in maternal urine were observed dramatically higher in NTDs population than that in normal controls (P < 0.01, P < 0.05, respectively). Moreover, DEHP treatment (10^-6 M) led to developmental toxicity in chick embryos via accelerating oxidative stress response and cell apoptosis, and changing the level of oxidative stress-related indicators. Moreover, high dose choline (100 μg/μl) could partially restrain the toxicity effects induced by DEHP. Our data collectively imply that the incidence of NTDs may closely associate with DEHP exposure, which disturbs the development of neural tubes by enhancing oxidative stress.

SUBMITTER: Song G

PROVIDER: S-EPMC7640930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPhthalates may disturb metabolic homeostasis in the liver by interfering with the peroxisome proliferator-activated receptors (PPARs). However, the role of hepatic macrophages in the lipid metabolic dysregulation induced by diethylhexyl phthalate (DEHP) remains unclear.ObjectivesWe aimed to evaluate the respective role of hepatocyte- and macrophage-specific PPARγ in the hepatotoxicity induced by DEHP.MethodsWild-type (WT), hepatocyte-specific PPARγ knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were administered DEHP (625mg/kg body weight) by daily gavage for 28 d, followed by hepatotoxicity examination and macrophage analysis. RNA sequencing and lipid metabolomic analysis were used to characterize the molecular changes in mouse liver. Mouse bone marrow-derived macrophages (BMDMs) and human monocytic THP-1 cell-derived macrophages were used to investigate the mechanistic regulation of macrophages' polarization by DEHP and mono(2-ethylhexyl) phthalate (MEHP).ResultsThe levels of hepatic steatosis and triglyceride were significantly higher in the mice treated with DEHP compared with the control mice in the WT and Hep-KO model. Lipid accumulation induced by DEHP was notably attenuated in the Mac-KO mice, but M2-polarization of hepatic macrophages in the Mac-KO mice was significantly higher compared with the WT mice under DEHP treatment. The M2-polarization of BMDMs and human macrophages was suppressed by DEHP and MEHP. Transcriptomic and lipidomic data suggested lower levels of lipid biosynthesis, fatty acid oxidation, and oxidative phosphorylation in the Mac-KO mice compared with the WT and Hep-KO mice under DEHP treatment.ConclusionsOur data suggested that the orchestrated activation of PPARα and PPARγ by MEHP may reprogram hepatic macrophages' polarization, thereby affecting lipid homeostasis in the mouse liver. Although this conclusion was based on studies conducted in mice and in vitro, these findings may aid in elucidating the health effect of environmental phthalate exposure. https://doi.org/10.1289/EHP9373.

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Diethylhexyl phthalate induces teratogenic effects through oxidative stress response in a chick embryo model.

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