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      Maternal immune response and air pollution exposure during pregnancy: insights from the Early Markers for Autism (EMA) study

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          Abstract

          Background

          Perinatal exposure to air pollution and immune system dysregulation are two factors consistently associated with autism spectrum disorders (ASD) and other neurodevelopmental outcomes. However, little is known about how air pollution may influence maternal immune function during pregnancy.

          Objectives

          To assess the relationship between mid-gestational circulating levels of maternal cytokines/chemokines and previous month air pollution exposure across neurodevelopmental groups, and to assess whether cytokines/chemokines mediate the relationship between air pollution exposures and risk of ASD and/or intellectual disability (ID) in the Early Markers for Autism (EMA) study.

          Methods

          EMA is a population-based, nested case–control study which linked archived maternal serum samples collected during weeks 15–19 of gestation for routine prenatal screening, birth records, and Department of Developmental Services (DDS) records. Children receiving DDS services for ASD without intellectual disability (ASD without ID; n = 199), ASD with ID (ASD with ID; n = 180), ID without ASD (ID; n = 164), and children from the general population (GP; n = 414) with no DDS services were included in this analysis. Serum samples were quantified for 22 cytokines/chemokines using Luminex multiplex analysis technology. Air pollution exposure for the month prior to maternal serum collection was assigned based on the Environmental Protection Agency’s Air Quality System data using the maternal residential address reported during the prenatal screening visit.

          Results

          Previous month air pollution exposure and mid-gestational maternal cytokine and chemokine levels were significantly correlated, though weak in magnitude (ranging from − 0.16 to 0.13). Ten pairs of mid-pregnancy immune markers and previous month air pollutants were significantly associated within one of the child neurodevelopmental groups, adjusted for covariates ( p < 0.001). Mid-pregnancy air pollution was not associated with any neurodevelopmental outcome. IL-6 remained associated with ASD with ID even after adjusting for air pollution exposure.

          Conclusion

          This study suggests that maternal immune activation is associated with risk for neurodevelopmental disorders. Furthermore, that prenatal air pollution exposure is associated with small, but perhaps biologically relevant, effects on maternal immune system function during pregnancy. Additional studies are needed to better evaluate how prenatal exposure to air pollution affects the trajectory of maternal immune activation during pregnancy, if windows of heightened susceptibility can be identified, and how these factors influence neurodevelopment of the offspring.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s11689-020-09343-0.

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          Most cited references43

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          Human health effects of air pollution.

          Hazardous chemicals escape to the environment by a number of natural and/or anthropogenic activities and may cause adverse effects on human health and the environment. Increased combustion of fossil fuels in the last century is responsible for the progressive change in the atmospheric composition. Air pollutants, such as carbon monoxide (CO), sulfur dioxide (SO(2)), nitrogen oxides (NOx), volatile organic compounds (VOCs), ozone (O(3)), heavy metals, and respirable particulate matter (PM2.5 and PM10), differ in their chemical composition, reaction properties, emission, time of disintegration and ability to diffuse in long or short distances. Air pollution has both acute and chronic effects on human health, affecting a number of different systems and organs. It ranges from minor upper respiratory irritation to chronic respiratory and heart disease, lung cancer, acute respiratory infections in children and chronic bronchitis in adults, aggravating pre-existing heart and lung disease, or asthmatic attacks. In addition, short- and long-term exposures have also been linked with premature mortality and reduced life expectancy. These effects of air pollutants on human health and their mechanism of action are briefly discussed.
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            Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.

            Exposure to prenatal infection has been suggested to cause deficiencies in fetal neurodevelopment. In this study we included all children born in Denmark from 1980, through 2005. Diagnoses of autism spectrum disorders (ASDs) and maternal infection were obtained through nationwide registers. Data was analyzed using Cox proportional hazards regression. No association was found between any maternal infection and diagnosis of ASDs in the child when looking at the total period of pregnancy: adjusted hazard ratio = 1.14 (CI: 0.96-1.34). However, admission to hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester were found to be associated with diagnosis of ASDs in the offspring, adjusted hazard ratio = 2.98 (CI: 1.29-7.15) and adjusted hazard ratio = 1.42 (CI: 1.08-1.87), respectively. Our results support prior hypotheses concerning early prenatal viral infection increasing the risk of ASDs.
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              Maternal immune activation and abnormal brain development across CNS disorders.

              Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies.
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                Author and article information

                Contributors
                hvolk1@jhu.edu
                Journal
                J Neurodev Disord
                J Neurodev Disord
                Journal of Neurodevelopmental Disorders
                BioMed Central (London )
                1866-1947
                1866-1955
                16 December 2020
                16 December 2020
                2020
                : 12
                : 42
                Affiliations
                [1 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Department of Mental Health, Wendy Klag Center for Autism and Developmental Disabilities, Bloomberg School of Public Health, , Johns Hopkins University, Kennedy Krieger Institute Intellectual and Developmental Disabilities Research Center, ; 624 N. Broadway, HH833, Baltimore, MD 21205 USA
                [2 ]GRID grid.253559.d, ISNI 0000 0001 2292 8158, Department of Public Health, , California State University, ; Fullerton, CA USA
                [3 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, UC Davis MIND Institute, , University of California Davis, ; Davis, CA USA
                [4 ]GRID grid.236815.b, ISNI 0000 0004 0442 6631, Environmental Health Investigations Branch, , California Department of Public Health, ; Richmond, CA USA
                [5 ]GRID grid.427236.6, ISNI 0000 0001 0294 3035, Sonoma Technology, Inc., ; Petaluma, CA USA
                [6 ]GRID grid.280062.e, ISNI 0000 0000 9957 7758, Division of Research, , Kaiser Permanente of Northern California, ; Oakland, CA USA
                Author information
                http://orcid.org/0000-0002-5415-2494
                Article
                9343
                10.1186/s11689-020-09343-0
                7745402
                33327930
                fbbfbcf1-6a5c-4937-8a0e-9c2aeb1eda73
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 16 March 2020
                : 13 November 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000073, Autism Speaks;
                Award ID: #8463
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: MH014592
                Funded by: FundRef http://dx.doi.org/10.13039/100000066, National Institute of Environmental Health Sciences;
                Award ID: 016669
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;
                Award ID: 079123
                Award ID: 079125
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Neurosciences
                air pollution,immune response,prenatal exposure,intellectual disability,autism spectrum disorder

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