Epidemiology has associated fine particulate matter(PM_(2.5))exposure with an increased cardiovascular risk.However,the underlying mechanism,particularly from the liver perspective,remains unclear.Here,the influence o...Epidemiology has associated fine particulate matter(PM_(2.5))exposure with an increased cardiovascular risk.However,the underlying mechanism,particularly from the liver perspective,remains unclear.Here,the influence of chronic PM_(2.5)exposure on cardiovascular risk in mice fed a high-fat and high-cholesterol diet(HFCD)was studied by using a real-world PM_(2.5)exposure system.Results showed that PM_(2.5)exposure elevated the serum levels of nonhigh-density lipoprotein cholesterol(non-HDL-C)and oxidized low-density lipoprotein(oxLDL)in HFCD-fed mice,demonstrating increased cardiovascular risk.To investigate the molecular mechanism,lipidomics and metabolomics analyses were conducted and revealed that PM_(2.5)exposure enhanced lipid accumulation and disturbed purine metabolism and glutathione metabolism in the liver of HFCD-fed mice,contributing to the elevated non-HDL-C levels and intensified oxidative stress.Moreover,PM_(2.5)exposure increased total cholesterol levels by upregulating Hmgcr expression and downregulating Cyp7a1 expression in the livers of HFCD-fed mice.The HDL-C level was reduced by inhibiting the hepatic Abca1 and Abcg1 expression and decreasing the levels of ApoA-I and LCAT.Additionally,the PM_(2.5)-induced pro-oxidative environment impeded the oxLDL clearance and further triggered inflammation,in turn exacerbating oxidative stress and oxLDL production.This study demonstrated a synergy of PM_(2.5)and HFCD on cardiovascular risk and illuminated the molecular mechanism in PM_(2.5)-susceptible populations.展开更多
Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the oc...Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the occurrence of CVD.The epigenetic mechanism of PM_(2.5)-triggered mitochondrial injury of cardiomyocytes is unclear.This study focused on the mi R-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM_(2.5).Results illustrated that PM_(2.5)impaired mitochondrial function and caused dynamics homeostasis imbalance.Besides,PM_(2.5)up-regulated mi R-421 and down-regulated SIRT3 gene expression,along with decreasing p-FOXO3a(SIRT3 downstream target gene)and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene Drp1.Further,mi R-421 inhibitor(mi R-421i)and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM_(2.5)exposure and mediated the expression of SOD2,OPA1 and Drp1,restoring the mitochondrial morphology and function.It suggests that mi R-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM_(2.5)and that mi R-421i and resveratrol exert protective effects against PM_(2.5)-incurred cardiotoxicity.展开更多
Simulation of fine particulate matter(PM_(2.5))exposure is essential for evaluating adverse health effects.In this work,an ambient exposure system that mimicked real atmospheric conditions was installed in Taiyuan,Chi...Simulation of fine particulate matter(PM_(2.5))exposure is essential for evaluating adverse health effects.In this work,an ambient exposure system that mimicked real atmospheric conditions was installed in Taiyuan,China to study impacts of chronic PM_(2.5) exposure on adult and aged mice as well as Sirtuin3 knockout(Sirt3 KO)mice and wild-type(WT)mice.The real-ambient exposure system eliminated the possible artificial effects caused from exposure experiments and maintained the physiochemical characteristics of PM_(2.5).The case studies indicated that aged mice exhibited apparent heart dysfunction involving in-creased heart rate and decreased blood pressure after 17-week of real-ambient PM_(2.5) exposure.Meanwhile,15-week of real-ambient PM_(2.5) exposure decreased the heart rate and amounts of associated catecholamines to induce heart failure in Sirt3 KO mice.Additionally,the increased pro-inflammatory cytokines and decreased platelet related indices suggested that inflammation occurred.The changes of biomarkers detected by targeted metabolomics confirmed metabolic disorder in WT and Sirt3 KO mice after exposed to real-ambient PM_(2.5).These results indicated that the real-ambient PM_(2.5) exposure system could evaluate the risks of certain diseases associated with air pollution and have great potential for support-ing the investigations of PM_(2.5) effects on other types of rodent models.展开更多
Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,t...Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,they are transferred across the placenta and fetal blood brain barrier,causing the adverse birth outcomes of offspring.This study demonstrated that the gestational exposure resulted in cognitive and emotional disorders in female offspring although the offspring were not exposed to PM_(2.5).Placental metabolic pathways modulated fetal brain development and played a pivotal role for maternal-placentalfetal interactions in the fetal programming of adult behavioral and mental disorders.Samples of fetus,offspring hippocampus and placenta from the mice exposed to PM_(2.5) were investigated using a comprehensive approach including mass spectrometry-based lipidomics and three-dimensional imaging.The exposure induced the neuro-degeneration in hippocampus,impairment of placental cytoarchitecture,and reprogramming of lipidome,which might affect the modulation of maternal-fetal cross-talk and result in the behavior disorders of offspring.The variation of spatial distribution of lipids was profoundly affected in dorsal pallium and hippocampal formation regions of fetal brain,offspring hippocampus,as well as labyrinth and junctional zones of placenta.The abundance alteration of lipid markers associated with neurodegenerative diseases was validated in transgenic mouse model with Alzheimer’s disease and human cerebrospinal fluid from patients with Parkinson’s disease.The finding could help with the selection of more suitable heterogeneous-related substructures targeting PM_(2.5) exposure and the exploration of PM_(2.5)-induced toxicological effects on neurodegenerative diseases.展开更多
Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic ...Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic mice(AD mice)were exposed to either filtered air(FA)or PM_(2.5)for eight weeks with a real-world exposure system in Taiyuan,China(mean PM_(2.5)concentration in the cage was 61μg/m~3).We found that PM_(2.5)exposure could remarkably aggravate AD mice's ethological and brain ultrastructural damage,along with the elevation of the pro-inflammatory cytokines(IL-6 and TNF-α),Aβ-42 and ACh E levels and the decline of Ch AT levels in the brains.Based on high-throughput sequencing results,some differentially expressed(DE)m RNAs and DE mi RNAs in the brains of AD mice after PM_(2.5)exposure were screened.Using RT-q PCR,seven DE mi RNAs(mmu-mi R-193b-5p,122b-5p,466h-3p,10b-5p,1895,384–5p,and 6412)and six genes(Pcdhgb8,Unc13b,Robo3,Prph,Pter,and Tbata)were evidenced the and verified.Two mi RNA-target gene pairs(mi R-125b-Pcdhgb8 pair and mi R-466h-3p-IL-17Rα/TGF-βR2/Aβ-42/ACh E pairs)were demonstrated that they were more related to PM_(2.5)-induced brain injury.Results of Gene Ontology(GO)pathways and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways predicted that synaptic and postsynaptic regulation,axon guidance,Wnt,MAPK,and m TOR pathways might be the possible regulatory mechanisms associated with pathological response.These revealed that PM_(2.5)-elevated pro-inflammatory cytokine levels and PM_(2.5)-altered neurotransmitter levels in AD mice could be the important causes of brain damage and proposed the promising mi RNA and m RNA biomarkers and potential mi RNA-m RNA interaction networks of PM_(2.5)-promoted AD.展开更多
基金supported by National Key Research and Development Program of China(2018YFA0901104)National Natural Science Foundation of China(91843301)+1 种基金Hong Kong General Research Fund(12302922,12303320,and 12103820)internal research funds SKLP_2223_P04 from Hong Kong Baptist University.
文摘Epidemiology has associated fine particulate matter(PM_(2.5))exposure with an increased cardiovascular risk.However,the underlying mechanism,particularly from the liver perspective,remains unclear.Here,the influence of chronic PM_(2.5)exposure on cardiovascular risk in mice fed a high-fat and high-cholesterol diet(HFCD)was studied by using a real-world PM_(2.5)exposure system.Results showed that PM_(2.5)exposure elevated the serum levels of nonhigh-density lipoprotein cholesterol(non-HDL-C)and oxidized low-density lipoprotein(oxLDL)in HFCD-fed mice,demonstrating increased cardiovascular risk.To investigate the molecular mechanism,lipidomics and metabolomics analyses were conducted and revealed that PM_(2.5)exposure enhanced lipid accumulation and disturbed purine metabolism and glutathione metabolism in the liver of HFCD-fed mice,contributing to the elevated non-HDL-C levels and intensified oxidative stress.Moreover,PM_(2.5)exposure increased total cholesterol levels by upregulating Hmgcr expression and downregulating Cyp7a1 expression in the livers of HFCD-fed mice.The HDL-C level was reduced by inhibiting the hepatic Abca1 and Abcg1 expression and decreasing the levels of ApoA-I and LCAT.Additionally,the PM_(2.5)-induced pro-oxidative environment impeded the oxLDL clearance and further triggered inflammation,in turn exacerbating oxidative stress and oxLDL production.This study demonstrated a synergy of PM_(2.5)and HFCD on cardiovascular risk and illuminated the molecular mechanism in PM_(2.5)-susceptible populations.
基金supported by the National Natural Science Foundation of China(No.22176116)the Natural Science Foundation of Shanxi Province in China(No.201801D121260)the Hundred Talents Program of Shanxi Province in China(2017-7)。
文摘Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the occurrence of CVD.The epigenetic mechanism of PM_(2.5)-triggered mitochondrial injury of cardiomyocytes is unclear.This study focused on the mi R-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM_(2.5).Results illustrated that PM_(2.5)impaired mitochondrial function and caused dynamics homeostasis imbalance.Besides,PM_(2.5)up-regulated mi R-421 and down-regulated SIRT3 gene expression,along with decreasing p-FOXO3a(SIRT3 downstream target gene)and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene Drp1.Further,mi R-421 inhibitor(mi R-421i)and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM_(2.5)exposure and mediated the expression of SOD2,OPA1 and Drp1,restoring the mitochondrial morphology and function.It suggests that mi R-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM_(2.5)and that mi R-421i and resveratrol exert protective effects against PM_(2.5)-incurred cardiotoxicity.
基金supported by the National Natural Science Foundation of China(Nos.91843301,91543202 and 21806025)collaborative research fund from the Research Grants Council of Hong Kong(No.C2014-14E)。
文摘Simulation of fine particulate matter(PM_(2.5))exposure is essential for evaluating adverse health effects.In this work,an ambient exposure system that mimicked real atmospheric conditions was installed in Taiyuan,China to study impacts of chronic PM_(2.5) exposure on adult and aged mice as well as Sirtuin3 knockout(Sirt3 KO)mice and wild-type(WT)mice.The real-ambient exposure system eliminated the possible artificial effects caused from exposure experiments and maintained the physiochemical characteristics of PM_(2.5).The case studies indicated that aged mice exhibited apparent heart dysfunction involving in-creased heart rate and decreased blood pressure after 17-week of real-ambient PM_(2.5) exposure.Meanwhile,15-week of real-ambient PM_(2.5) exposure decreased the heart rate and amounts of associated catecholamines to induce heart failure in Sirt3 KO mice.Additionally,the increased pro-inflammatory cytokines and decreased platelet related indices suggested that inflammation occurred.The changes of biomarkers detected by targeted metabolomics confirmed metabolic disorder in WT and Sirt3 KO mice after exposed to real-ambient PM_(2.5).These results indicated that the real-ambient PM_(2.5) exposure system could evaluate the risks of certain diseases associated with air pollution and have great potential for support-ing the investigations of PM_(2.5) effects on other types of rodent models.
基金supported by the Second Tibetan Plateau Scientific Expedition and Research Program(2019QZKK0304-02)Joint Chinese Academy of Sciences(CAS)-Max Planck Society(MPG)Research Project(HZXM20225001MI)+3 种基金the Strategic Priority Research Program A of Chinese Academy of Sciences(XDA20050104)the National Natural Science Foundation of China(42041005)CAS Light of West China Programthe Fundamental Research Funds for the Central Universities。
基金supported by the National Natural Science Foundation of China(91843301)the National Key Research Program of China(2017YFC1600505 and 2017YFE0191000)+1 种基金Sanming Project of Medicine in Shenzhen of China(SZSM201811070)General Research Fund from Hong Kong Research Grants Council(12303320)。
文摘Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,they are transferred across the placenta and fetal blood brain barrier,causing the adverse birth outcomes of offspring.This study demonstrated that the gestational exposure resulted in cognitive and emotional disorders in female offspring although the offspring were not exposed to PM_(2.5).Placental metabolic pathways modulated fetal brain development and played a pivotal role for maternal-placentalfetal interactions in the fetal programming of adult behavioral and mental disorders.Samples of fetus,offspring hippocampus and placenta from the mice exposed to PM_(2.5) were investigated using a comprehensive approach including mass spectrometry-based lipidomics and three-dimensional imaging.The exposure induced the neuro-degeneration in hippocampus,impairment of placental cytoarchitecture,and reprogramming of lipidome,which might affect the modulation of maternal-fetal cross-talk and result in the behavior disorders of offspring.The variation of spatial distribution of lipids was profoundly affected in dorsal pallium and hippocampal formation regions of fetal brain,offspring hippocampus,as well as labyrinth and junctional zones of placenta.The abundance alteration of lipid markers associated with neurodegenerative diseases was validated in transgenic mouse model with Alzheimer’s disease and human cerebrospinal fluid from patients with Parkinson’s disease.The finding could help with the selection of more suitable heterogeneous-related substructures targeting PM_(2.5) exposure and the exploration of PM_(2.5)-induced toxicological effects on neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China(No.91843301)the Hundred Talents Program of Shanxi Province in China,and the Hong Kong Research Grants Council Research Matching Scheme(RMGS2019-1-12,RMGS-2019-1-15)。
文摘Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic mice(AD mice)were exposed to either filtered air(FA)or PM_(2.5)for eight weeks with a real-world exposure system in Taiyuan,China(mean PM_(2.5)concentration in the cage was 61μg/m~3).We found that PM_(2.5)exposure could remarkably aggravate AD mice's ethological and brain ultrastructural damage,along with the elevation of the pro-inflammatory cytokines(IL-6 and TNF-α),Aβ-42 and ACh E levels and the decline of Ch AT levels in the brains.Based on high-throughput sequencing results,some differentially expressed(DE)m RNAs and DE mi RNAs in the brains of AD mice after PM_(2.5)exposure were screened.Using RT-q PCR,seven DE mi RNAs(mmu-mi R-193b-5p,122b-5p,466h-3p,10b-5p,1895,384–5p,and 6412)and six genes(Pcdhgb8,Unc13b,Robo3,Prph,Pter,and Tbata)were evidenced the and verified.Two mi RNA-target gene pairs(mi R-125b-Pcdhgb8 pair and mi R-466h-3p-IL-17Rα/TGF-βR2/Aβ-42/ACh E pairs)were demonstrated that they were more related to PM_(2.5)-induced brain injury.Results of Gene Ontology(GO)pathways and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways predicted that synaptic and postsynaptic regulation,axon guidance,Wnt,MAPK,and m TOR pathways might be the possible regulatory mechanisms associated with pathological response.These revealed that PM_(2.5)-elevated pro-inflammatory cytokine levels and PM_(2.5)-altered neurotransmitter levels in AD mice could be the important causes of brain damage and proposed the promising mi RNA and m RNA biomarkers and potential mi RNA-m RNA interaction networks of PM_(2.5)-promoted AD.
