ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Ying Wang,An-Liang Guo,Yang Xu,Xiaoyan Xu,Lin Yang,Yang Yang,Lan Chao
Background 2-ethylhexyldiphenyl phosphate (EHDPP) was used widespread in recent years and it was reported to impair reproductive behaviors and decrease fertility in male Japanese medaka. However, whether EHDPP causes spermatogenesis disturbance remains uncertain. Objectives We aimed to study the male reproductive toxicity of EHDPP and its related mechanism. Methods Human spermatocyte cell line GC-2 was treated with 10 µM, 50 µM or 100 µM EHDPP for 24 h. Male CD-1 mice aged 6 weeks were given 1, 10, or 100 mg/kg/d EHDPP daily for 42 days and then euthanized to detect sperm count and motility. Proliferation, apoptosis, oxidative stress was detected in mice and cell lines. Metabolome and transcriptome were used to detect the related mechanism. Finally, anti-oxidative reagent N-Acetylcysteine was used to detect whether it could reverse the side-effect of EHDPP both in vivo and in vitro . Results Our results showed that EHDPP inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Metabolome and transcriptome showed that nucleotide metabolism disturbance and DNA damage was potentially involved in EHDPP-induced reproductive toxicity. Finally, we found that excessive ROS production caused DNA damage and mitochondrial dysfunction; NAC supplement reversed the side effects of EHDPP such as DNA damage, proliferation inhibition, apoptosis and decline in sperm motility. Conclusion ROS-evoked DNA damage and nucleotide metabolism disturbance mediates EHDPP-induced germ cell proliferation inhibition and apoptosis, which finally induced decline of sperm motility.
研究领域:
毒理学
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生殖生物学
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分子生物学
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Jin Yan,Yuning Zhang,Anyu Ni,Zukang Yu,Ziqi Liu,Shihan Zhang,Shanshan Di,Zhiyuan Meng,Qiuhui Qian,Zejun Wang,Sen Yan,Huili Wang
Chronic EHDPP exposure impairs behavior through gut–brain axis disruption. • EHDPP reshapes gut microbiota and compromises intestinal integrity. • Microbial dysbiosis triggers neuroinflammation and BBB impairment. • Altered tryptophan and tyrosine metabolism underlies behavioral deficits. • Integrated analyses identify a microbiota-mediated neurotoxicity pathway. Environmental pollutants are increasingly associated with neurological dysfunction, yet their underlying mechanisms remain poorly understood. Here, zebrafish were used to investigate the chronic lifelong neurotoxicity of 2-ethylhexyl diphenyl phosphate (EHDPP) exposure at two sublethal levels of 5 and 125 μg/L. EHDPP exposure induced pronounced sex-specific neurobehavioral deficits, with females exhibiting greater susceptibility to locomotor dysfunction, social impairment, and cognitive decline. Mechanistically, EHDPP reshaped the gut microbial community by enriching pro-inflammatory Gram-negative Fusobacteria while depleting beneficial Firmicutes and Bacteroidetes taxa, accompanied by intestinal barrier disruption, lipopolysaccharide translocation, intestinal inflammation, and blood-brain barrier impairment. These alterations further triggered microglia and astrocyte-mediated neuroinflammation and extensive disturbances in neurotransmitter metabolism, characterized by targeted detection of forty-two brain metabolites, particularly within tryptophan- and tyrosine-associated pathways. Integrated analyses of 16S gut microbiota sequencing, targeted brain metabolomics, and multi-dimensional behavioral tests revealed a coordinated regulatory network linking microbial dysbiosis, inflammatory signaling, neurotransmitter imbalance, and neurobehavioral abnormalities. Notably, dietary inulin supplementation effectively restored microbial homeostasis, alleviated peripheral and central inflammation and neurotransmitter disturbances, and ameliorated EHDPP-induced behavioral impairments, providing direct evidence that the gut-brain axis acts as a key mediator of EHDPP-induced neurotoxicity. Our study also highlights microbiota-targeted intervention as a potential strategy for mitigating pollutant-associated neurological disorders. Download: Download high-res image (225KB) Download: Download full-size image
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DOI
高影响因子
Toxics
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2026
·Vol. 14
·期 8
·691
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IF 4.9
Zhao Zhou,Hongbin Gao,Shunda Zhu,Lvlue Cai,Yijing Chen,Keqi Hu,Yungang Liu
As a commonly present organophosphorus flame retardant and persistent organic pollutant, 2-ethylhexyl diphenyl phosphate (EHDPP) has been observed to be genotoxic in cultured human hepatoma (HepG2) cells which depends on CYP activities. Yet, its impacts on hepatic Cyp expression, hepatotoxicity and genotoxicity in intact mammalians remain unidentified. In this study, adult male C57BL/6J mice received EHDPP by gastric gavage at doses of 50, 100, and 150 mg/kg (b.w.)/d for 7 d, then the hepatic expression of several Cyp proteins, aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) was analyzed by Western blotting; hepatoxicity was determined by serum ALT/AST activities and hepatic histological examination, while genotoxicity by comet assay, phosphorylated histone (γ-H2AX) protein, micronucleus test, and Pig-a assay. A micronucleus test in mouse hepatoma (Hepa1-6) cells in vitro was employed to observe the modulating effect of PCB 126 (100 nM)/BAY-218 (700 nM) (Ahr-Cyp1a1 activator/inhibitor). The results indicated that EHDPP induced hepatic Cyp1a1, 2e1, AhR, Cyp1a2, Cyp3a4 and PXR proteins and histologic liver damage at 50 mg/kg/d and/or higher doses, while at the highest dose (150 mg/kg/d) with hepatic DNA damage and micronucleus formation in bone marrow polychromatic erythrocytes. The result of Pig-a assay (at 14 and 28 d) was negative. In Hepa1-6 cells EHDPP induced micronucleus marginally; however, this effect was enhanced by PCB 126, while abolished by BAY-218. This study suggests that EHDPP may enhance protein expression of hepatic Cyp1a1, Cyp2e1, AhR and PXR and induce liver damage and DNA/chromosome damage in mice; Cyp1a1 might be a major activating enzyme.
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Environmental Chemistry and Ecotoxicology
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2025
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IF 8.2
Miaocui Xi,Xue Bai,Lu Fang,Xuedong Wang,Jin Yan,Qiuhui Qian,Zejun Wang,Huili Wang
Herein, we systematically compared the cardiotoxicity effects of two structurally similar organophosphate flame retardants (OPFRs; EHDPP and its major metabolite DPHP) using zebrafishi as a model organism. Predictive toxicity data from two aquatic species, together with empirical LC₅₀ values obtained in zebrafish larvae, consistently demonstrated that 2-ethylhexyl diphenyl phosphate (EHDPP) is substantially more toxic than diphenyl phosphate (DPHP). At LC₅₀-scaled concentrations, both contaminants induced the reduced heart rate, pericardial edema, and cardiac malformations, in concomitant with enhanced activities of creatine kinase (CK) and lactate dehydrogenase (LDH) and downregulated cardiac transcription factors ( gata4 and Nkx2.5 ) and upregulated structural gene cmlc2 . Even at low concentrations, EHDPP triggered apoptosis and elevated reactive oxygen species (ROS) levels in cardiac and pericardial tisues, along with prominent lipid accumulation in the heart, vasculature, and intersegmental arteries. It activated multiple pathways including MAPK, calcium signaling, and excitation-contraction coupling, while DPHP primarily affected cardiac function via calcium pump regulation and neuro-signaling pathways. Disease ontology (DO) enrichment analysis revealed that both EHDPP and DPHP associated target genes were most significantly enriched in cardiovascular-related diseases. Pharmacological rescue experiments using pathway-specific agents (Y-27632 and isoproterenol) further validated the functional roles of key signaling pathways in mediating the observed cardiotoxicity. Albeit differing in only one alkyl chain, EHDPP and DPHP displayed significantly differential cardiotoxicity and molecular mechanisms in zebrafish. These observations are conducive to illustrating OPFRs' structure-activity relationship and their health risk.
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Yanan Zhang,Fei Meng,Tiantian Zhao,Jingyi Du,Naigang Li,Xinghui Qiao,Yuan Yao,Dong Wu,Fan Peng,Dongshuang Wang,Shuang Yang,Jiaming Shi,Ruoxi Liu,Wenjuan Zhou,Lei Li,Aijun Hao
2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.
研究领域:
生殖毒理学
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细胞生物学
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分子生物学
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内分泌学
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高影响因子
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