Effects Of Gestational Exposure To Glufosinate Ammonium On Gut Microbiome And Neurodevelopment In Offspring

Impairment to the dynamics of neurodevelopment could lead to intellectual disability and behavioral abnormality,which are known as neurodevelopmental disorders(NDDs).This spectrum of diseases damage the language,cognition and motor functions,and finally result in reduced social adaption in affected individuals.Patients suffer from poor quality of life and heavy burden is caused to the society.Etiological researches recognized environmental chemical exposure during early life as an important risk factor for NDDs.Pesticides are chemicals used for pest control and protection of both crops and plants.Organophosphate(OP)pesticides are among the kinds with the most consumption.Glufosinate ammonium(GLA)is a novel kind of organophosphate herbicides,which is used widely as the alternate for glyphosate.Exposure to GLA is extremely common in human,including pregnant women and children.Increasing evidences indicate that gestational exposure to OP pesticides was associated the development of NDDs.Despite the well-documented neurotoxicity caused by acute GLA exposure,data on the effects of gestational exposure to GLA on neurodevelopment is rather limited.Gut microbiota is the entirety of bacteria in human intestine.Previous researches have linked gut microbiota to system health in humans.In recent years,the association between microbiome and central nervous system has been gradually recognized,and has been a new research focus in neuroscience.Disturbed microbiome could interact with human brain and influence host behaviors via metabolism,and further leads to NDDs like autism spectrum disorder(ASD),schizophrenia,neurodegenerative diseases,etc.Exploring the role of gut microbiome in the development and progress of NDDs could provide novel insights into the prevention and control of the diseases.Given the fact that exogenous chemicals could disturb gut microbiome,and gut microbiome could influence host neurodevelopment,we proposed a new research hypothesis here: gestational exposure to GLA could damage gut microbiome along with related metabolism and further induce neurodevelopmental abnormality.In this study,we firstly conducted a meta-analysis on the effects of gestational exposure to OP pesticides on neurodevelopment.Subsequently,we chose GLA as a representative OP pesticide,which was commonly detected in pregnant women and newborns,and built mouse model prenatally exposed to GLA.Behavioral tests were performed to assess neurodevelopment and gut microbiome along with its metabolism was profiled.This study aimed to provide complementary data for OP toxicity,and to promote the safe use of GLA.Part I Gestational Exposure to Organophosphate Pesticides and Neurodevelopment in Offspring: a Meta-Analysis ObjectiveOrganophosphate(OP)pesticides are widely used in agricultural and household pest control around the world.The potential health effects of OP pesticides continue to be an important public health issue.Increasing epidemiological evidences indicated that OP pesticides could impair child neurodevelopment,while inconsistent results existed as well.Here we conducted a meta-analysis on available researches in order to clarify the association between gestational exposure to organophosphate pesticides and neurodevelopment in offspring.MethodsWe searched for researches regarding OP pesticides and their effects on neurodevelopment from three online databases(Pub Med?Web of Science?Cochrane Library)before August 1st,2018.Records were screened and those met the exclusion criteria were removed.Data was extracted from all included publications.Quality of research was assessed by STROBE tool.Random-effect model was used to combine effect sizes,and publication bias was also tested.ResultsA total of 11 publications were included in quantitative analysis,which were of good quality.Meta-analysis found that ?DAP and ?DEP levels in maternal urine during pregnancy were inversely associated with child cognitive development,but not motor development.Maternal ?DEP levels were associated with poorer full-scale IQ,processing speed and perceptual reasoning.In addition,maternal ?DAP,?DMP and ?DEP levels were all positively associated with abnormal reflexes in newborns.No significant publication bias was observed.ConclusionExposure to OP pesticides during pregnancy was associated with child cognitive development damage and abnormal reflexes in newborns.Future studies are supposed to confirm the findings from current study,and to focus on the effects of targeted OPs pesticide exposure during pregnancy on offspring neurodevelopment.Part II Effects of Gestational Exposure to Glufosinate Ammonium on Gut Microbiome and Neurodevelopment in Offspring Mice ObjectiveAbnormal neurodevelopment caused by early life exposure to pesticides is recognized as an important public health issue.Our previous study suggested that organophosphate pesticides could impair child neurobehavioral development.Glufosinate ammonium(GLA)is a widely used organophosphate herbicide,which could be commonly detected in body fluids of both pregnant women and newborns.Existing evidences indicate that GLA has reproductive toxicity,while data concerning the effects of gestational GLA exposure on neurodevelopment is rather limited and the mechanism is largely unknown.Here we employed a mouse model exposed to GLA prenatally to clarify the effects of gestational exposure to GLA on neurodevelopment in offspring mice,and explored the underlying mechanism in view of gut microbiome and corresponding metabolic functions.MethodsFemale ICR mice were treated with GLA through drinking water for 8 weeks,and then mated with male mice.GLA administration lasted until delivery.Behavioral tests were carried out in offspring mice after 6 weeks old.16 S r RNA gene sequencing was used to profile gut microbiome.Fecal microbiota transplant experiments were performed to explore the association between gut microbiome and behavior outcomes.Finally,we conducted metabolomics analysis to profile the fingerprints of metabolome of gut microbiota,and to identify the changed metabolic pathways and metabolites.ResultsReduced locomotor activity,impaired memory formation and autism-like behaviors were observed in GLA-treated offspring mice.Marked alternation in gut microbiome of the treatment offspring mice could be found at 4th week after birth.However,the disturbed gut microbiome seemed to recover over time.Fecal microbiota transplant experiments confirmed that gut microbiome mediated the GLA-induced toxicity on neurodevelopment.Fecal metabolomics analysis indicated remarkable changes in microbiome-related metabolism in the treatment group,and pathway analysis further identified three disturbed metabolic pathways,including pyrimidine metabolism,retinol metabolism and fatty acid biosynthesis.These pathways were acknowledged to be associated with neurodevelopment,which could be the cause of behavioral abnormality in mice.ConclusionPresent study suggested that gestational exposure to GLA disturbed gut microbiome and metabolism,and thereby induced behavioral abnormalities in mice.More efforts are warranted to improve the risk assessment of GLA exposure and clarify its health effects on human beings.