Persistently Upregulated Hippocampal mTOR Signals Mediated by Fecal SCFAs Impair Memory in Male Pups with SMM Exposure in Utero
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摘要
Objective To investigate the molecular mechanisms of the adverse effects of exposure to sulfamonomethoxin(SMM) in pregnancy on the neurobehavioral development of male offspring. Methods Pregnant mice were randomly divided into four groups: control‐(normal saline), low‐ [10 mg/(kg.day)], middle‐ [50 mg/(kg.day)], and high‐dose [200 mg/(kg.day)] groups, which received SMM by gavage daily during gestational days 1‐18. We measured the levels of short‐chain fatty acids(SCFAs) in feces from dams and male pups. Furthermore, we analyzed the mR NA and protein levels of genes involved in the mammalian target of rapamycin(m TOR) pathway in the hippocampus of male pups by RT‐PCR or Western blotting. Results Fecal SCFA concentrations were significantly decreased in dams. Moreover, the production of individual fecal SCFAs was unbalanced, with a tendency for an increased level of total fecal SCFAs in male pups on postnatal day(PND) 22 and 56. Furthermore, the phosphatidylinositol 3‐kinase(PI3 k)/protein kinase B(AKT)/mTOR or mT OR/ribosomal protein S6 kinase 1(S6 K1)/4 EBP1 signaling pathway was continuously upregulated until PND 56 in male offspring. In addition, the expression of Sepiapterin Reductase(SPR), a potential target of m TOR, was inhibited. Conclusion In utero exposure to SMM, persistent upregulation of the hippocampal mTOR pathway related to dysfunction of the gut(SCFA)‐brain axis may contribute to cognitive deficits in male offspring.
Objective To investigate the molecular mechanisms of the adverse effects of exposure to sulfamonomethoxin(SMM) in pregnancy on the neurobehavioral development of male offspring. Methods Pregnant mice were randomly divided into four groups: control‐(normal saline), low‐ [10 mg/(kg.day)], middle‐ [50 mg/(kg.day)], and high‐dose [200 mg/(kg.day)] groups, which received SMM by gavage daily during gestational days 1‐18. We measured the levels of short‐chain fatty acids(SCFAs) in feces from dams and male pups. Furthermore, we analyzed the mR NA and protein levels of genes involved in the mammalian target of rapamycin(m TOR) pathway in the hippocampus of male pups by RT‐PCR or Western blotting. Results Fecal SCFA concentrations were significantly decreased in dams. Moreover, the production of individual fecal SCFAs was unbalanced, with a tendency for an increased level of total fecal SCFAs in male pups on postnatal day(PND) 22 and 56. Furthermore, the phosphatidylinositol 3‐kinase(PI3 k)/protein kinase B(AKT)/mTOR or mT OR/ribosomal protein S6 kinase 1(S6 K1)/4 EBP1 signaling pathway was continuously upregulated until PND 56 in male offspring. In addition, the expression of Sepiapterin Reductase(SPR), a potential target of m TOR, was inhibited. Conclusion In utero exposure to SMM, persistent upregulation of the hippocampal mTOR pathway related to dysfunction of the gut(SCFA)‐brain axis may contribute to cognitive deficits in male offspring.
Objective To investigate the molecular mechanisms of the adverse effects of exposure to sulfamonomethoxin(SMM) in pregnancy on the neurobehavioral development of male offspring. Methods Pregnant mice were randomly divided into four groups: control‐(normal saline), low‐ [10 mg/(kg.day)], middle‐ [50 mg/(kg.day)], and high‐dose [200 mg/(kg.day)] groups, which received SMM by gavage daily during gestational days 1‐18. We measured the levels of short‐chain fatty acids(SCFAs) in feces from dams and male pups. Furthermore, we analyzed the mR NA and protein levels of genes involved in the mammalian target of rapamycin(m TOR) pathway in the hippocampus of male pups by RT‐PCR or Western blotting. Results Fecal SCFA concentrations were significantly decreased in dams. Moreover, the production of individual fecal SCFAs was unbalanced, with a tendency for an increased level of total fecal SCFAs in male pups on postnatal day(PND) 22 and 56. Furthermore, the phosphatidylinositol 3‐kinase(PI3 k)/protein kinase B(AKT)/mTOR or mT OR/ribosomal protein S6 kinase 1(S6 K1)/4 EBP1 signaling pathway was continuously upregulated until PND 56 in male offspring. In addition, the expression of Sepiapterin Reductase(SPR), a potential target of m TOR, was inhibited. Conclusion In utero exposure to SMM, persistent upregulation of the hippocampal mTOR pathway related to dysfunction of the gut(SCFA)‐brain axis may contribute to cognitive deficits in male offspring.
引文
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43.Gao J,Xiong B,Zhang B,et al.Sulforaphane Alleviates Lipopolysaccharide‐induced Spatial Learning and Memory Dysfunction in Mice:The Role of BDNF‐m TOR Signaling Pathway.Neuroscience,2018;388,357‐66.
2.Zhang QQ,Ying GG,Pan CG,et al.Comprehensive evaluation of antibiotics emission and fate in the river basins of China:source analysis,multimedia modeling,and linkage to bacterial resistance.Environ Sci Technol,2015;49,6772‐82.
3.Ahmed MB,Rajapaksha AU,Lim JE,et al.Distribution and accumulative pattern of tetracyclines and sulfonamides in edible vegetables of cucumber,tomato,and lettuce.J Agric Food Chem,2015;63,398‐405.
4.Yang Y,Song W,Lin H,et al.Antibiotics and antibiotic resistance genes in global lakes:A review and meta‐analysis.Environ Int,2018;116,60‐73.
5.Wang H,Wang B,Zhao Q,et al.Antibiotic body burden of Chinese school children:a multisite biomonitoring‐based study.Environ Sci Technol,2015;49,5070‐9.
6.Slykerman RF,Thompson J,Waldie KE,et al.Antibiotics in the first year of life and subsequent neurocognitive outcomes.Acta Paediatrica,2017;106,87‐94.
7.Leclercq S,Mian FM,Stanisz AM,et al.Low‐dose penicillin in early life induces long‐term changes in murine gut microbiota,brain cytokines and behavior.Nat Commun,2017;8,15062.
8.Bailey LC,Forrest CB,Zhang P,et al.Association of Antibiotics in Infancy With Early Childhood Obesity.Jama Pediatrics,2014;168,1063‐9.
9.Hviid A,Svanstr MH,Frisch M.Antibiotic use and inflammatory bowel diseases in childhood.Gut,2011;60,49‐54.
10.Zhang Q,Zhang D,Ye K,et al.Physiological and behavioral responses in offspring mice following maternal exposure to sulfamonomethoxine during pregnancy.Neurosci Lett,2016;624,8‐16.
11.Fr?Hlich EE,Farzi A,Mayerhofer R,et al.Cognitive impairment by antibiotic‐induced gut dysbiosis:Analysis of gut microbiota‐brain communication.Brain Behav Immunity,2016;56,140‐55.
12.Jernberg C,Lofmark S,Edlund C,et al.Long‐term ecological impacts of antibiotic administration on the human intestinal microbiota.ISME J,2007;1,56‐66.
13.Gonzalez‐perez G,Hicks AL,Tekieli TM,et al.Maternal Antibiotic Treatment Impacts Development of the Neonatal Intestinal Microbiome and Antiviral Immunity.J Immunol,2016;196,3768‐79.
14.Butler MI,Cryan JF,Dinan TG.Man and the Microbiome:ANew Theory of Everything?Annu Rev Clin Psychol,2019;online.
15.Forsythe P,Kunze W,Bienenstock J.Moody microbes or fecal phrenology:what do we know about the microbiota‐gut‐brain axis?Bmc Medicine,2016;14,58.
16.Collins SM,Surette M,Bercik P.The interplay between the intestinal microbiota and the brain.Nat Rev Microbiol,2012;10,735‐42.
17.Frost G,Sleeth ML,Sahuriarisoylu M,et al.The short‐chain fatty acid acetate reduces appetite via a central homeostatic mechanism.Nat Commun,2014;5,3611.
18.Govindarajan N,Agis‐balboa RC,Walter J,et al.Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression.J Alzheimers Dis,2011;26,187‐97.
19.Maqsood R,Stone TW.The Gut‐Brain Axis,BDNF,NMDA and CNS Disorders.Neurochem Res,2016;41,2819‐35.
20.Psichas A,Sleeth ML,Murphy KG,et al.The short chain fatty acid propionate stimulates GLP‐1 and PYY secretion via free fatty acid receptor 2 in rodents.Int J Obes,2015;39,424‐9.
21.Wong M.Mammalian target of rapamycin(mTOR)pathways in neurological diseases.Biomed J,2013;36,40‐50.
22.Caccamo A,Majumder S,Richardson A,et al.Molecular interplay between mammalian target of rapamycin(m TOR),amyloid‐beta,and Tau:effects on cognitive impairments.J Biol Chem,2010;285,13107‐20.
23.Halloran J,Hussong SA,Burbank R,et al.Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non‐cognitive components of behavior throughout lifespan in mice.Neuroscience,2012;223,102‐13.
24.Tang Y,Chen Y,Jiang H,et al.Short‐chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria‐mediated apoptotic cell death.Autophagy,2011;18,602‐18.
25.Kulcsar A,Matis G,Molnar A,et al.Effects of butyrate on the insulin homeostasis of chickens kept on maize‐or wheat‐based diets.Acta Vet Hung,2016;64,482‐96.
26.Wu B,Duan LC,Luo HQ,et al.Study on the safety of sulfamonomethoxin in yellow‐feathered broiler chickens.Breeding and Feed,2015;1,13‐5.(In Chinese)
27.Zhang Q.Early life exposure to antibiotic induces abnormal behavior in offspring mice:the regulatory mechanism of m TORsignaling pathway in the gut‐brain axis.2017.(In Chinese)
28.Li Q,Han Y,Abc D,et al.The Gut Microbiota and Autism Spectrum Disorders.Frontiers in Cellular Neuroscience,2017;11,120.
29.Schulfer AF,Battaglia T,Alvarez Y,et al.Intergenerational transfer of antibiotic‐perturbed microbiota enhances colitis in susceptible mice.Nat Microbiol,2017;3,234‐42.
30.Perry RJ,Peng L,Barry NA,et al.Acetate mediates a microbiome‐brain‐beta‐cell axis to promote metabolic syndrome.Nature,2016;534,213‐7.
31.De Vadder F,Kovatcheva‐Datchary P,Goncalves D,et al.Microbiota‐generated metabolites promote metabolic benefits via gut‐brain neural circuits.Cell,2014;156,84‐96.
32.Shultz SR,Macfabe DF,Martin S,et al.Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long‐Evans rat:further development of a rodent model of autism.Behav Brain Res,2009;200,33‐41.
33.Wang L,Christophersen CT,Sorich MJ,et al.Elevated Fecal Short Chain Fatty Acid and Ammonia Concentrations in Children with Autism Spectrum Disorder.Dig Dis Sci,2012;57,2096‐102.
34.Kim K,Kim H,Yim J.Functional analysis of sepiapterin reductase in Drosophila melanogaster.Pteridines,2015;26,63‐8.
35.Kwak SS,Jeong M,Choi JH,et al.Amelioration of behavioral abnormalities in BH(4)‐deficient mice by dietary supplementation of tyrosine.PLoS One,2013;8,e60803.
36.Tramutola A,Triplett JC,Di Domenico F,et al.Alteration of m TOR signaling occurs early in the progression of Alzheimer disease(AD):analysis of brain from subjects with pre‐clinical AD,amnestic mild cognitive impairment and late‐stage AD.JNeurochem,2015;133,739‐49.
37.Caccamo A,De Pinto V,Messina A,et al.Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease‐like cognitive and pathological deficits by restoring hippocampal gene expression signature.J Neurosci,2014;34,7988‐98.
38.Wang S,Zhou SL,Min FY,et al.m TOR‐mediated hyperphosphorylation of tau in the hippocampus is involved in cognitive deficits in streptozotocin‐induced diabetic mice.Metabolic Brain Disease,2014;29,729‐36.
39.Troca‐Marin JA,Alves‐Sampaio A,Montesinos ML.Deregulated m TOR‐mediated translation in intellectual disability.Prog Neurobiol,2012;96,268‐82.
40.Ehninger D.From genes to cognition in tuberous sclerosis:implications for mTOR inhibitor‐based treatment approaches.Neuropharmacology,2013;68,97‐105.
41.Iyer AM,Van Scheppingen J,Milenkovic I,et al.m TORHyperactivation in down syndrome hippocampus appears early during development.J Neuropathol Exp Neurol,2014;73,671‐83.
42.Zhang JC,Yao W,Hashimoto K.Brain‐derived Neurotrophic Factor(BDNF)‐TrkB Signaling in Inflammation‐related Depression and Potential Therapeutic Targets.Curr Neuropharmacol,2016;14,721‐31.
43.Gao J,Xiong B,Zhang B,et al.Sulforaphane Alleviates Lipopolysaccharide‐induced Spatial Learning and Memory Dysfunction in Mice:The Role of BDNF‐m TOR Signaling Pathway.Neuroscience,2018;388,357‐66.