RESUMO
Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.
Assuntos
Ferroptose , Macrófagos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Transdução de Sinais , Baço , Animais , Humanos , Masculino , Camundongos , Ferroptose/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/citologia , Baço/metabolismoRESUMO
Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.
Assuntos
Aquaporina 1 , Mucosa Intestinal , Animais , Aquaporina 1/genética , Aquaporina 1/metabolismo , Camundongos , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Inflamação/genética , Inflamação/induzido quimicamente , Masculino , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , NF-kappa B/metabolismo , NF-kappa B/genética , Dietilexilftalato/toxicidade , Ácidos Ftálicos , Transdução de Sinais/efeitos dos fármacosRESUMO
INTRODUCTION: Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. OBJECTIVES: Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. METHODS: We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe2+ levels and glutathione system to confirm the occurrence of ferroptosis. RESULTS: In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. CONCLUSION: Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and "The Global Plastic Toxicity Debt".
RESUMO
Atrazine (ATZ) is the most prevalent herbicide that has been widely used in agriculture to control broadleaf weeds and improve crop yield and quality. The heavy use of ATZ has caused serious environmental pollution and toxicity to human health. Lycopene (LYC), is a carotenoid that exhibits numerous health benefits, such as prevention of cardiovascular diseases and nephropathy. However, it remains unclear that whether ATZ causes cardiorenal injury or even cardiorenal syndrome (CRS) and the beneficial role of LYC on it. To test this hypothesis, mice were treated with LYC and/or ATZ for 21 days by oral gavage. This study demonstrated that ATZ exposure caused cardiorenal morphological alterations, and several inflammatory cell infiltrations mediated by activating NF-κB signaling pathways. Interestingly, dysregulation of MAPK signaling pathways and MAPK phosphorylation caused by ATZ have been implicated in cardiorenal diseases. ATZ exposure up-regulated cardiac and renal injury associated biomarkers levels that suggested the occurrence of CRS. However, these all changes were reverted, and the phenomenon of CAR was disappeared by LYC co-treatment. Based on our findings, we postulated a novel mechanism to elucidate pesticide-induced CRS and indicated that LYC can be a preventive and therapeutic agent for treating CRS by targeting MAPK/NF-κB signaling pathways.
Assuntos
Atrazina , Síndrome Cardiorrenal , Humanos , Camundongos , Animais , Licopeno/metabolismo , Atrazina/toxicidade , NF-kappa B , Síndrome Cardiorrenal/induzido quimicamente , Estresse OxidativoRESUMO
As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment.
Assuntos
Dietilexilftalato , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ácidos Ftálicos , Humanos , Animais , Camundongos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Receptor 4 Toll-Like/metabolismo , Chaperonina 60/farmacologia , Piroptose , Dietilexilftalato/toxicidade , Baço/metabolismo , Camundongos Endogâmicos ICRRESUMO
Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
Assuntos
Dietilexilftalato , Ácidos Ftálicos , Humanos , Dietilexilftalato/toxicidade , Dietilexilftalato/metabolismo , Mitocôndrias/metabolismo , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/metabolismo , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Hidrolases/metabolismoRESUMO
Di-(2-ethylhexyl) phthalate (DEHP), an extensively used plasticizer, can cause environmental pollution and organ injury. Lycopene (LYC) is a natural carotene that has the potential to prevent chronic diseases. To reveal the effect of DEHP and/or LYC on the kidney, male mice were treated with LYC (5 mg/kg) and/or DEHP (500 mg/kg or 1000 mg/kg) by gavage for 28 days. The study indicated that DEHP caused glomerular atrophy, tubular expansion, disappearance of the mitochondrial membrane, and cristae rupture. DEHP exposure can increase the expression of aquaporin (AQP) subunits and the activity of Ca2+-Mg2+-ATPase and decrease the activity of Na+-K+-ATPase, which results in ion disorder. However, LYC can relieve kidney injury by regulating the activity of ATPase, the expression of ATPase subunits, and AQP subunit expression. The results indicated that AQP was a target for LYC in antagonizing the disturbance of DEHP-induced renal damage.
Assuntos
Aquaporinas , Dietilexilftalato , Animais , Dietilexilftalato/toxicidade , Homeostase , Rim , Licopeno , Masculino , CamundongosRESUMO
Taking the seedlings of Quercus glauca, a dominant evergreen broadleaf tree species in subtropical area, as test materials, this paper studied their photosynthesis, chlorophyll fluorescence, and chlorophyll content under effects of simulated acid rain with pH 2.5, 4.0, and 5.6 (CK). After 2-year acid rain stress, the net photosynthetic rate of Q. glauca increased significantly with decreasing pH of acid rain. The acid rain with pH 2.5 and 4.0 increased the stomatal conductance and transpiration rate, and the effect was more significant under pH 2.5. The intercellular CO2 concentration decreased in the order of pH 2.5 > pH 5.6 > pH 4.0. The maximum photosynthetic rate, light compensation point, light saturation point, and dark respiration rate were significantly higher under pH 2.5 and 4.0 than under pH 5.6, while the apparent quantum yield was not sensitive to acid rain stress. The maximal photochemical efficiency of PS II and the potential activity of PS II under pH 2.5 and 4.0 were significantly higher than those under pH 5.6. The relative chlorophyll content was in the order of pH 2.5 > pH 5.6 > pH 4.0, and there was a significant difference between pH 2.5 and 4.0. All the results suggested that the photosynthesis and chlorophyll fluorescence of Q. glauca increased under the effects of acid rain with pH 2.5 and 4.0, and the acid rain with pH 2.5 had more obvious effects.