Young children and the developing fetus are especially vulnerable to adverse environmental exposures [1, 2]. Pollution and environmental chemicals are recognized as causing substantial mortality  and adding substantially to the burden of disease . While traditional pollutants, such as ambient and indoor air pollution, persistent organic pollutants, heavy metals, and pesticides are well recognized as contributing to ill health , there is an increasing recognition that a wider view of all environmental contributors to adverse health outcomes is required. The concept that individual toxicants rarely act alone in increasing disease risk but that all exposures must be considered is gaining traction. The totality of exposures is often referred to as the “exposome.” [5, 6] The exposome includes exposure to xenobiotic toxicants, endogenous stressors resulting from exogenous exposures, toxic metabolites of exposures, dietary constituents, and psychological and physical stressors, as well as their biological responses.
Since the 1950s the world has experienced an “explosion” of synthetic chemicals introduced into our environment. While many of these have made lives easier, the safety of the vast majority of these chemicals was not tested prior to their introduction. The toxicity of many chemicals and their adverse effects on human health may only become apparent after years of use. The use of some chemicals has been banned, for example some persistent organic pollutants have been banned under the Stockholm convention [http://www.pops.int/], however many others continue to be used and untested alternatives to banned substances are frequently used. Two classes of chemical attracting recent attention are the per- and polyfluoroalkylated substances (PFAS) and the short half-life plastics additives, plasticizers, bisphenols and phthalates.
PFAS are ubiquitous in modern environments and commonly reported in human biomonitoring studies . They are used to provide non-stick, waterproof and greaseproof surfaces on consumer products and have been widely used in fire-fighting foams . Human exposure primarily occurs via contaminated drinking water, although exposure can also occur through contaminated dust, air, and foods . In some countries, including the USA and Australia, large populations have been exposed to PFAS-contaminated drinking water, yet direct evidence of adverse health effects is scarce and controversial. Epidemiological studies have reported associations between PFAS exposures and various adverse health effects, including altered immune and thyroid function, liver disease, lipid and insulin dysregulation, kidney disease, adverse reproductive and developmental outcomes, and cancer . Exposures during pregnancy have been associated with pregnancy complications, including hypertension and preeclampsia, and low birth weight in the offspring . Studies in children have reported associations between PFAS exposure and febrile infections , respiratory tract infections , and asthma . Prenatal exposures have also been associated with impaired vaccine responsiveness in early childhood , atopic dermatitis and increased respiratory and urinary infections in girls . Results from different studies are not always consistent [13, 15, 16], with some showing effects in girls but not in boys [15, 17].
Bisphenols and phthalates have endocrine-disrupting properties that adversely impact human health [18, 19, 20]. While these compounds have short half-lives the ubiquitous nature of their presence in modern environments mean that essentially all humans have blood levels of these compounds, and they can be measured in urine . Ingested bisphenols are rapidly metabolised in the liver to an inactive conjugated form and many studies do not distinguish between free (active) bisphenols and total bisphenols. However, active free bisphenols can routinely be detected in human biomonitoring studies . Free bisphenols also readily cross the placenta, influence placental gene expression, and can be measured in cord blood [23, 24, 25, 26]. Early literature concentrated on bisphenol A but other bisphenols, including bisphenol S, bisphenol F, and bisphenol AF have attracted recent attention and have the same endocrine disrupting properties as bisphenol A . Similarly, both low and high molecular weight phthalates cross the placenta, can be measured in cord blood, and have adverse effects on the developing fetus and children [19, 27, 28, 29, 30, 31]. Longitudinal human birth cohort studies have contributed much to our knowledge of the adverse consequences of environmental exposures during fetal development and in early postnatal life.
This paper will discuss three important, but different, linkages between environmental exposures and immune functioning. Firstly, we will present important data from the Hokkaido Study on Environment and Children’s Health showing that chemical exposure in early life is associated with increased risk of infection and immunologically driven health outcomes. Next, we will explore the evidence for air pollution exposure and risk of Covid-19. Lastly, we will discuss how air pollution can induce oxidative stress, a process driven by the immune system, and how individuals with a genetic predisposition to oxidative stress may be most at risk of the harmful effects of air pollution.
The Hokkaido study includes two birth cohorts, an initial cohort consisting of 514 pregnant women, recruited from one hospital in Sapporo between 2002 and 2005 at second to third trimester, and a second cohort, consisting of 20 926 pregnant women at gestational age <13 weeks, recruited from 37 hospitals in Hokkaido between 2003 and 2012 . The objectives of the study were:
The study focused on persistent organic pollutants, in other words, environmental chemicals with long half-lives, such as dioxins and polychlorinated bisphenols, organochlorine pesticides, such as DDT, PFAS and endocrine-disrupting chemicals with short half-lives but ubiquitous exposure, such as phthalate esters, bisphenols and organophosphate flame retardants . Major findings from the study related to the immune functions to date include:
Children in the Hokkaido study are currently adolescents and follow up is planned to continue into adult life. We look forward to more important findings from this study.
Since the onset of the Covid-19 pandemic there has been an explosion in publications dealing with many aspects of the Sars – Cov2 virus, clinical features of Covid-19, and epidemiological studies addressing factors increasing susceptibility to and severity of Covid-19. Knowledge in many areas remains limited, including why children were relatively spared, an unusual situation with respiratory viruses . Following initial observations between poorer air quality and increased Covid-19 mortality in the USA , the issue of whether air pollution increases susceptibility to, and severity of Covid-19 has attracted much attention. Indeed, a PubMed search conducted on September 8th 2021 using the terms “Covid-19” and “air pollution” showed that 554 articles had been published in 2020 and 690 published to date in 2021. Of these 80 in 2020 and 107 in 2021 claimed to be systematic reviews.
An association between Covid-19 and air pollution is certainly supported by the literature but is not simple. For example, some of the most polluted mega-cities in India, Bangladesh, and Africa were not initially epicentres of Covid-19. Examination of standardised mortality rates from Covid-19 for 10 age groups showed a correlation with particulate matter with a mass median aerodynamic diameter (PM10) [β 0.147 (95% CI 0.059–0.234), p = 0.001] across 36 Italian provinces . Furthermore, measures of long-term air quality (2016-2019) across 71 Italian provinces showed associations between case numbers of Covid-19 and annual average NO2 (R2 = 0.247, p < 0.01), PM2.5 (R2 = 0.340, p < 0.01), PM10 (R2 = 0.267, p < 0.01) exposure .
Travaglio et al.  examined associations between air pollution in the UK, using either 2018 data or 5-year average data, and Covid-19 cases and mortality. Using population data, the main contributor of Covid-19 was NO2, with a 1µg/m3 increase in NO2 in 2018 associated with a 3.3% increase in cases and 3.1% increase in deaths. Restricting the study population to participants in the UK-Biobank, where data were available at an individual level, showed that for every unit increase in PM2.5 and PM10, the number of Covid-19 cases increased by 1.7% and 11.7%, respectively . In general, the associations between air pollutants and Covid-19 cases and mortality were similar when 5-year average exposures were used instead of 2018 data. This raises the question of whether long-term air pollution exposure is more strongly associated with Covid-19 cases and mortality than short-term exposure. This was partly addressed in a Chinese study where the association between air pollution exposure and daily Covid-19 case rates were examined with lags between 0-7 days, 0-14 days, and 0-21 days . For PM2.5, PM10, CO, and NO2 the associations were stronger with longer lags between exposure and cases . These data are consistent with a study from New York City that showed no associations between PM2.5 and Covid deaths with a lag of 0-1 day . In contrast, there was a significant association between moving average O3 (ppb) exposure and new Covid-19 cases. A one unit increase in moving average O3 was associated with as 10.5% increase in new cases . One short-term exposure associated with increased Covid-19 cases is exposure to wildfire smoke. Kiser et al.  studied case rates of Covid-19 in Reno, Nevada, associated with a major wildfire. They reported that a 10µg/m3 increase in wildfire PM2.5 was associated with a 6.3% relative increase in SARS-Cov2 positive test rate. A review of 26 articles from many countries showed associations between short term air pollution exposure and increased cases of Covid-19, suggesting an increase in viral transmission . In the same review long-term air pollution exposure was associated with increases severity and mortality . One possible mechanism for this association could be alterations in the airway epithelium that make it respond to SARS-Cov2 infection with a more pro-inflammatory response. Evidence is emerging that both particulate matter and covid-19 induce angiotensin II-dependent proinflammatory cytokine production. The lung contains type II alveolar cells that express angiotensin-converting enzyme 2 receptors (ACE2). SARS-CoV-2 binds to these receptors, and through the renin-angiotensin axis induces inflammation. Particulate matter has been shown in preclinical studies to upregulate the same pathway, and lead to production of the same cytokines see in the covid-19 induced cytokine storm, thus there is the potential for both particulate matter and SARS-CoV-2 to be triggering the same pro-inflammatory targets .
The Lancet Commission report on Pollution and Health highlighted the major contribution pollution makes to global mortality and morbidity . Air pollution is a major contributor to childhood deaths from pneumonia and adult deaths from chronic obstructive pulmonary disease. Evidence shows that long-term exposure to PM10, SO2 and NO2 is associated with an increased risk of tuberculosis, potentially through local damage to the lungs which makes them more susceptible to Mycobacterium tuberculosis infection . The physical properties of air pollution reduce ultraviolet-B intensity at ground level, which has been linked to lower vitamin D synthesis . Adequate vitamin D is required for healthy immune function, and lower levels of vitamin D have been associated with several infectious diseases including tuberculosis . Air pollution contributes to poor respiratory health in a number of ways, with periods of particular developmental susceptibility being during fetal development and in early postnatal life . Exposures occurring during fetal development (maternal exposures) result in impaired fetal growth and impaired lung growth, both of which result in low lung function at birth [54, 55, 56, 57]. Exposures in early life result in increased respiratory infections, reduced lung function growth and increase life-long risk of acute and chronic respiratory disease [1, 2, 57, 58, 59, 60].
While the epidemiological evidence linking air pollution exposure to poor respiratory health, including increased respiratory infections, is strong, evidence for the precise mechanisms involved is less developed. Children exposed to high levels of traffic related air pollution show biomarkers of oxidative damage in exhaled breath , and those with reduced or null function variations in genes related to antioxidant defence show increased adverse health effects when exposed to air pollution [62, 63]. Taken together, these data suggest that the adverse effect of air pollution on respiratory health are mediated, in part, via oxidant damage in the airways.
Oxygen is an oxidant gas and the lungs have developed elaborate mechanisms to defend against oxidant stimuli. In the lungs epithelial lining fluid-containing mucus and high levels of the reduced form of glutathione provides the first line of antioxidant defence. This is augmented by enzymes that detoxify xenobiotics and dietary antioxidants, such as vitamin C. Oxidant exposures result in the production of reactive oxygen species (ROS) in the lungs. ROS are generated by neutrophils and macrophages as part of the body defence against invading microorganisms. These “intrinsic” ROS can contribute to overwhelming antioxidant defences and contribute to oxidant damage. The term “oxidative stress” is used to describe the situation where the body’s antioxidant defences are overwhelmed by ROS, resulting in tissue damage .
Air pollution is a complex mixture of solid, gaseous, and chemical components. Particles generally have a carbonaceous core, to which chemicals and oxidant radicals can be bound. These may include transition metals, oxidant chemicals, persistent organic pollutants, and other toxicants. The composition of particulate matter is influenced by what is burnt and how efficient the combustion process was. A relatively newly discovered oxidant product of incomplete combustion are environmentally persistent free radicals [65, 66]. These are the subject of another publication in this series and will not be discussed further here. PM entering the lungs can induce direct epithelial damage, reducing the effectiveness of the epithelial barrier, reduce mitochondrial function via inducing oxidative stress, and directly stimulate inflammatory pathways. O3 and NO2 are more likely to exert their effects via stimulation of inflammatory pathways, with resultant ROS generation and induction of oxidative stress .
Oxidative damage to the respiratory epithelium is a likely mechanism linking air pollution exposure to increased risk of respiratory infection . Impaired barrier function would allow greater access for invading microbes to the epithelial cells and sub-epithelial layers. Oxidant damage to epithelial cells may reduce the production of anti-microbial peptides, reducing anti-viral and anti-bacterial defences. Induced mitochondrial dysfunction results in reduced ATP production and increased cell death, potentially allowing greater microbial spread from cell to cell. Induction of pro-inflammatory pathways further increases ROS generation and cell dysfunction. One additional potential mechanism by which air pollution can increase risk of respiratory infections is via interfering with anti-microbial activity of Vitamin D . This activity comes, in part, via upregulating transcription of the cathelicidin gene to produce the cathelicidin peptide. This is cleaved to form a cationic peptide, known as LL37, which binds to microbes, punching holes in susceptible bacteria or destroying the envelope of enveloped viruses, such as Sars-Cov2. Fine particles in air pollution appear to inactivate LL37, possibly by changing it from a cationic to a neutral peptide, removing its anti-microbial activity, and facilitating viral replication.
The Pacific Basin Consortium 2021 Focus Meeting allowed research teams to come together and share valuable insights on environmental health. This paper summarises a session exploring environmental impacts on infectious disease and shows the importance of a range of environmental exposures to human health. The Hokkaido Study on Environment and Children’s Health is an invaluable birth cohort in the field of children’s environmental health and, as shown here, has generated high quality evidence of the negative association between environmental chemicals and children’s immune function. Long-time follow-up is warranted to examine how effects last and later onset of diseases. The evidence of air pollution’s role in both infectious diseases generally, and COVID-19 specifically, is well developed. The role of oxidative stress as a mediator between environmental exposures and immune health is emerging as key mechanism of interest. Globally, we find ourselves in a time of unprecedented environmental change while simultaneously adapting to the on-going effects of the Covid-19 pandemic. Understanding the complex interplay between the immune system and the environment is important to protecting public health across all populations.
The authors have no competing interests to declare.
Sly P, Blake T, Islam Z. Impact of prenatal and early life environmental exposures on normal human development. Paediatr Respir Rev.; 2021. DOI: https://doi.org/10.1016/j.prrv.2021.05.007
Sly PD, Carpenter DO, Van den Berg M, et al. Health Consequences of Environmental Exposures: Causal Thinking in Global Environmental Epidemiology. Annals of Global Health. 2016; 82(1): 3–9. DOI: https://doi.org/10.1016/j.aogh.2016.01.004
Landrigan PJ, Fuller R, Acosta NJR, et al. The Lancet Commission on pollution and health. Lancet. 2018; 391(10119): 462–512. DOI: https://doi.org/10.1016/S0140-6736(17)32345-0
Prüss-Ustün A, Vickers C, Haefliger P, Bertollini R. Knowns and unknowns on burden of disease due to chemicals: a systematic review. Environ Health. 2011; 10(9). DOI: https://doi.org/10.1186/1476-069X-10-9
Escher BI, Hackermüller J, Polte T, et al. From the exposome to mechanistic understanding of chemical-induced adverse effects. Environ Int. 2017; 99: 97–106. DOI: https://doi.org/10.1016/j.envint.2016.11.029
Vermeulen R, Schymanski EL, Barabási AL, Miller GW. The exposome and health: Where chemistry meets biology. Science. 2020; 367(6476): 392–396. DOI: https://doi.org/10.1126/science.aay3164
Pelch KE, Reade A, Wolffe TAM, Kwiatkowski CF. PFAS health effects database: Protocol for a systematic evidence map. Environ Int. 2019; 130: 104851. DOI: https://doi.org/10.1016/j.envint.2019.05.045
Domingo JL, Nadal M. Human exposure to per- and polyfluoroalkyl substances (PFAS) through drinking water: A review of the recent scientific literature. Environ Res. 2019; 177: 108648. DOI: https://doi.org/10.1016/j.envres.2019.108648
Fenton SE, Ducatman A, Boobis A, et al. Per- and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research. Environ Toxicol Chem. 2021; 40(3): 606–630. DOI: https://doi.org/10.1002/etc.4890
Blake BE, Fenton SE. Early life exposure to per- and polyfluoroalkyl substances (PFAS) and latent health outcomes: A review including the placenta as a target tissue and possible driver of peri- and postnatal effects. Toxicology. 2020; 443: 152565. DOI: https://doi.org/10.1016/j.tox.2020.152565
Dalsager L, Christensen N, Husby S, et al. Association between prenatal exposure to perfluorinated compounds and symptoms of infections at age 1-4years among 359 children in the Odense Child Cohort. Environ Int. 2016; 96: 58–64. DOI: https://doi.org/10.1016/j.envint.2016.08.026
Huang H, Yu K, Zeng X, et al. Association between prenatal exposure to perfluoroalkyl substances and respiratory tract infections in preschool children. Environ Res. 2020; 191: 110156. DOI: https://doi.org/10.1016/j.envres.2020.110156
Jackson-Browne MS, Eliot M, Patti M, Spanier AJ, Braun JM. PFAS (per- and polyfluoroalkyl substances) and asthma in young children: NHANES 2013–2014. Int J Hyg Environ Health. 2020; 229: 113565. DOI: https://doi.org/10.1016/j.ijheh.2020.113565
Granum B, Haug LS, Namork E, et al. Pre-natal exposure to perfluoroalkyl substances may be associated with altered vaccine antibody levels and immune-related health outcomes in early childhood. J Immunotoxicol. 2013; 10(4): 373–9. DOI: https://doi.org/10.3109/1547691X.2012.755580
Impinen A, Longnecker MP, Nygaard UC, et al. Maternal levels of perfluoroalkyl substances (PFASs) during pregnancy and childhood allergy and asthma related outcomes and infections in the Norwegian Mother and Child (MoBa) cohort. Environ Int. 2019; 124: 462–472. DOI: https://doi.org/10.1016/j.envint.2018.12.041
Impinen A, Nygaard UC, Lødrup Carlsen KC, et al. Prenatal exposure to perfluoralkyl substances (PFASs) associated with respiratory tract infections but not allergy- and asthma-related health outcomes in childhood. Environ Res. 2018; 160: 518–523. DOI: https://doi.org/10.1016/j.envres.2017.10.012
Kvalem HE, Nygaard UC, Lødrup Carlsen KC, Carlsen KH, Haug LS, Granum B. Perfluoroalkyl substances, airways infections, allergy and asthma related health outcomes – implications of gender, exposure period and study design. Environ Int. 2020; 134: 105259. DOI: https://doi.org/10.1016/j.envint.2019.105259
Braun JM. Early-life exposure to EDCs: role in childhood obesity and neurodevelopment. Nat Rev Endocrinol. 2017; 13(3): 161–173. DOI: https://doi.org/10.1038/nrendo.2016.186
Kahn LG, Philippat C, Nakayama SF, Slama R, Trasande L. Endocrine-disrupting chemicals: implications for human health. Lancet Diabetes Endocrinol. 2020; 8(8): 703–718. DOI: https://doi.org/10.1016/S2213-8587(20)30129-7
Abraham A, Chakraborty P. A review on sources and health impacts of bisphenol A. Rev Environ Health. 2020; 35(2): 201–210. DOI: https://doi.org/10.1515/reveh-2019-0034
Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJ, Schoenfelder G. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect. 2010; 118(8): 1055–70. DOI: https://doi.org/10.1289/ehp.0901716
Minatoya M, Sasaki S, Araki A, et al. Cord Blood Bisphenol A Levels and Reproductive and Thyroid Hormone Levels of Neonates: The Hokkaido Study on Environment and Children’s Health. Epidemiology. 2017; 28 (Suppl 1): S3–s9. DOI: https://doi.org/10.1097/EDE.0000000000000716
Sol CM, Santos S, Duijts L, et al. Fetal phthalates and bisphenols and childhood lipid and glucose metabolism. A population-based prospective cohort study. Environ Int. 2020; 144: 106063. DOI: https://doi.org/10.1016/j.envint.2020.106063
Speidel JT, Xu M, Abdel-Rahman SZ. Bisphenol A (BPA) and bisphenol S (BPS) alter the promoter activity of the ABCB1 gene encoding P-glycoprotein in the human placenta in a haplotype-dependent manner. Toxicol Appl Pharmacol. 2018; 359: 47–54. DOI: https://doi.org/10.1016/j.taap.2018.09.022
van den Berg M, Sly PD. Protecting the human fetus against effects of bisphenol A. lancet diabetes endocrinol. 2013; 1(2): 87–9. DOI: https://doi.org/10.1016/S2213-8587(13)70105-0
Gascon M, Casas M, Morales E, et al. Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy. J Allergy Clin Immunol. 2015; 135(2): 370–8. DOI: https://doi.org/10.1016/j.jaci.2014.09.030
Jøhnk C, Høst A, Husby S, et al. Maternal phthalate exposure and asthma, rhinitis and eczema in 552 children aged 5 years; a prospective cohort study. Environ Health. 2020; 19(1): 32. DOI: https://doi.org/10.1186/s12940-020-00586-x
Kolatorova L, Vitku J, Vavrous A, et al. Phthalate metabolites in maternal and cord plasma and their relations to other selected endocrine disruptors and steroids. Physiol Res. 2018; 67(Suppl 3): S473–s487. DOI: https://doi.org/10.33549/physiolres.933962
Lyche JL, Gutleb AC, Bergman A, et al. Reproductive and developmental toxicity of phthalates. J Toxicol Environ Health B Crit Rev. 2009; 12(4): 225–49. DOI: https://doi.org/10.1080/10937400903094091
Araki A, Mitsui T, Miyashita C, et al. Association between maternal exposure to di(2-ethylhexyl) phthalate and reproductive hormone levels in fetal blood: The Hokkaido Study on environment and children’s health. PLoS One. 2014; 9(10): e109039. DOI: https://doi.org/10.1371/journal.pone.0109039
Kishi R, Sasaki S, Yoshioka E, et al. Cohort profile: the Hokkaido study on environment and children’s health in Japan. Int J Epidemiol. 2011; 40(3): 611–8. DOI: https://doi.org/10.1093/ije/dyq071
Kishi R, Ikeda-Araki A, Miyashita C, et al. Hokkaido birth cohort study on environment and children’s health: cohort profile 2021. Environmental Health and Preventive Medicine. 2021; 26(1): 59–59. DOI: https://doi.org/10.1186/s12199-021-00980-y
Kishi R, Araki A, Minatoya M, et al. The Hokkaido Birth Cohort Study on Environment and Children’s Health: cohort profile-updated 2017. Environ Health Prev Med. 2017; 22(1): 46. DOI: https://doi.org/10.1186/s12199-017-0654-3
Okada E, Sasaki S, Saijo Y, et al. Prenatal exposure to perfluorinated chemicals and relationship with allergies and infectious diseases in infants. Environ Res. 2012; 112: 118–25. DOI: https://doi.org/10.1016/j.envres.2011.10.003
Inoue K, Okada F, Ito R, et al. Perfluorooctane sulfonate (PFOS) and related perfluorinated compounds in human maternal and cord blood samples: assessment of PFOS exposure in a susceptible population during pregnancy. Environ Health Perspect. 2004; 112(11): 1204–7. DOI: https://doi.org/10.1289/ehp.6864
Miyashita C, Bamai YA, Araki A, et al. Prenatal exposure to dioxin-like compounds is associated with decreased cord blood IgE and increased risk of wheezing in children aged up to 7years: The Hokkaido study. Sci Total Environ. 2018; 610–611: 191–199. DOI: https://doi.org/10.1016/j.scitotenv.2017.07.248
Miyashita C, Sasaki S, Saijo Y, et al. Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy. Environ Res. 2011; 111(4): 551–8. DOI: https://doi.org/10.1016/j.envres.2011.01.021
Ait Bamai Y, Goudarzi H, Araki A, et al. Effect of prenatal exposure to per- and polyfluoroalkyl substances on childhood allergies and common infectious diseases in children up to age 7 years: The Hokkaido study on environment and children’s health. Environ Int. 2020; 143: 105979. DOI: https://doi.org/10.1016/j.envint.2020.105979
Ait Bamai Y, Araki A, Kawai T, et al. Exposure to phthalates in house dust and associated allergies in children aged 6-12years. Environ Int. 2016; 96: 16–23. DOI: https://doi.org/10.1016/j.envint.2016.08.025
Sly PD, Trottier B, Carpenter D, et al. Children’s Environmental Health in South and Southeast Asia: Networking for Better Child Health Outcomes. Annals of Global Health. 2019; 85(1): 17. DOI: https://doi.org/10.5334/aogh.2403
Wu X, Nethery RC, Sabath MB, Braun D, Dominici F. Air pollution and COVID-19 mortality in the United States: Strengths and limitations of an ecological regression analysis. Sci Adv. 2020; 6(45). DOI: https://doi.org/10.1126/sciadv.abd4049
Dettori M, Deiana G, Balletto G, et al. Air pollutants and risk of death due to COVID-19 in Italy. Environ Res. 2021; 192: 110459. DOI: https://doi.org/10.1016/j.envres.2020.110459
Fattorini D, Regoli F. Role of the chronic air pollution levels in the Covid-19 outbreak risk in Italy. Environ Pollut. 2020; 264: 114732. DOI: https://doi.org/10.1016/j.envpol.2020.114732
Travaglio M, Yu Y, Popovic R, Selley L, Leal NS, Martins LM. Links between air pollution and COVID-19 in England. Environ Pollut. 2021; 268(Pt A): 115859. DOI: https://doi.org/10.1016/j.envpol.2020.115859
Zhu Y, Xie J, Huang F, Cao L. Association between short-term exposure to air pollution and COVID-19 infection: Evidence from China. Sci Total Environ. 2020; 727: 138704. DOI: https://doi.org/10.1016/j.scitotenv.2020.138704
Adhikari A, Yin J. Short-Term Effects of Ambient Ozone, PM(2.5), and Meteorological Factors on COVID-19 Confirmed Cases and Deaths in Queens, New York. Int J Environ Res Public Health. 2020; 17(11). DOI: https://doi.org/10.3390/ijerph17114047
Kiser D, Elhanan G, Metcalf WJ, Schnieder B, Grzymski JJ. SARS-CoV-2 test positivity rate in Reno, Nevada: association with PM2.5 during the 2020 wildfire smoke events in the western United States. J Expo Sci Environ Epidemiol. 2021; 31(5): 797–803. DOI: https://doi.org/10.1038/s41370-021-00366-w
Ali N, Islam F. The Effects of Air Pollution on COVID-19 Infection and Mortality-A Review on Recent Evidence. Front Public Health. 2020; 8: 580057. DOI: https://doi.org/10.3389/fpubh.2020.580057
Mescoli A, Maffei G, Pillo G, et al. The Secretive Liaison of Particulate Matter and SARS-CoV-2. A Hypothesis and Theory Investigation. Frontiers in Genetics. 2020; 11 (Hypothesis and Theory). DOI: https://doi.org/10.3389/fgene.2020.579964
Xiang K, Xu Z, Hu Y-Q, et al. Association between ambient air pollution and tuberculosis risk: A systematic review and meta-analysis. Chemosphere. 2021; 277: 130342. DOI: https://doi.org/10.1016/j.chemosphere.2021.130342
Rahman A, Elmi A. Air pollutants are negatively associated with vitamin D-synthesizing UVB radiation intensity on the ground. Scientific Reports. 2021; 11(1): 21480. DOI: https://doi.org/10.1038/s41598-021-00980-6
Aibana O, Huang C-C, Aboud S, et al. Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis. PLOS Medicine. 2019; 16(9): e1002907. DOI: https://doi.org/10.1371/journal.pmed.1002907
Goldizen FC, Sly PD, Knibbs LD. Respiratory effects of air pollution on children. Pediatric Pulmonology. 2015; 51: 94–108. DOI: https://doi.org/10.1002/ppul.23262
Hansen CA, Barnett AG, Pritchard G. The effect of ambient air pollution during early pregnancy on fetal ultrasonic measurements during mid-pregnancy. Environ Health Perspect. 2008; 116(3): 362–9. DOI: https://doi.org/10.1289/ehp.10720
Latzin P, Roosli M, Huss A, Kuehni CE, Frey U. Air pollution during pregnancy and lung function in newborns: a birth cohort study. The European Respiratory Journal. 2009; 33(3): 594–603. DOI: https://doi.org/10.1183/09031936.00084008
Stern G, Latzin P, Roosli M, et al. A prospective study of the impact of air pollution on respiratory symptoms and infections in infants. American Journal of Respiratory and Critical Care Medicine. 2013; 187(12): 1341–8. DOI: https://doi.org/10.1164/rccm.201211-2008OC
Boeyen J, Callan AC, Blake D, et al. Investigating the relationship between environmental factors and respiratory health outcomes in school children using the forced oscillation technique. International Journal of Hygiene and Environmental Health. 2017; 220(2): 494–502. DOI: https://doi.org/10.1016/j.ijheh.2017.01.014
Gasana J, Dillikar D, Mendy A, Forno E, Ramos Vieira E. Motor vehicle air pollution and asthma in children: a meta-analysis. Environ Res. 2012; 117: 36–45. DOI: https://doi.org/10.1016/j.envres.2012.05.001
Hehua Z, Qing C, Shanyan G, Qijun W, Yuhong Z. The impact of prenatal exposure to air pollution on childhood wheezing and asthma: A systematic review. Environ Res. 2017; 159: 519–530. DOI: https://doi.org/10.1016/j.envres.2017.08.038
Romieu I, Barraza-Villarreal A, Escamilla-Nunez C, et al. Exhaled breath malondialdehyde as a marker of effect of exposure to air pollution in children with asthma. J Allergy Clin Immunol. 2008; 121(4): 903–909.e6. DOI: https://doi.org/10.1016/j.jaci.2007.12.004
MacIntyre EA, Brauer M, Melen E, et al. GSTP1 and TNF Gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) study. Environ Health Perspect. 2014; 122(4): 418–24. DOI: https://doi.org/10.1289/ehp.1307459
Ungvari I, Hadadi E, Virag V, et al. Relationship between air pollution, NFE2L2 gene polymorphisms and childhood asthma in a Hungarian population. Journal of Community Genetics. 2012; 3(1): 25–33. DOI: https://doi.org/10.1007/s12687-011-0075-8
Betteridge DJ. What is oxidative stress? Metabolism. 2000; 49(2, Supplement 1): 3–8. DOI: https://doi.org/10.1016/S0026-0495(00)80077-3
Lee GI, Saravia J, You D, et al. Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection. Particle and Fibre Toxicology. 2014; 11: 57. DOI: https://doi.org/10.1186/s12989-014-0057-1
Stephenson EJ, Ragauskas A, Jaligama S, et al. Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice. American Journal of Physiology Endocrinology and Metabolism. 2016; 310(11): E1003–15. DOI: https://doi.org/10.1152/ajpendo.00521.2015
Kelly FJ. Oxidative stress: its role in air pollution and adverse health effects. Occupational and Environmental Medicine. 2003; 60(8): 612. DOI: https://doi.org/10.1136/oem.60.8.612
Woodby B, Arnold MM, Valacchi G. SARS-CoV-2 infection, COVID-19 pathogenesis, and exposure to air pollution: What is the connection? Ann N Y Acad Sci. 2021; 1486(1): 15–38. DOI: https://doi.org/10.1111/nyas.14512
Crane-Godreau MA, Clem KJ, Payne P, Fiering S. Vitamin D Deficiency and Air Pollution Exacerbate COVID-19 Through Suppression of Antiviral Peptide LL37. Frontiers in Public Health. 2020; 8: 232. DOI: https://doi.org/10.3389/fpubh.2020.00232