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Article Excerpt
BACKGROUND: Children who reside in agricultural settings are potentially exposed to higher levels of organophosphate (OP) pesticides, endotoxin, and allergens than their urban counterparts. Endotoxin and allergens stimulate maturation of the immune response in early childhood, but little is known about the effect of exposures to OPs or to the three combined.
OBJECTIVES: In this study, we investigated the relationships between these exposures and T-helper 1 (Th1) and T-helper 2 (Th2) cytokines, biomarkers of allergic asthma, in the subjects of CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas), a longitudinal birth cohort in Salinas Valley, California. Exposures were ascertained by interviewer-administered questionnaires and by home visits, and clinical diagnoses were abstracted from medical records. Blood samples were collected at 12 and 24 months of age and analyzed for Th1/Th2 status by flow cytometric detection of intracellular interferon-[gamma]/interleukin-4 cytokine expression.
FINDINGS: Mean Th2 levels were significantly higher in children with doctor-diagnosed asthma and children with wheezing at 2 years of age. In a multiple linear regression model, exclusive breast-feeding at 1 month and pet ownership were associated with 35.3% (p < 0.01) and 34.5% (p = 0.01) increases in Th1, respectively. Maternal agricultural work and presence of gas stove in the home were associated with a 25.9% increase (p = 0.04) and 46.5% increase (p < 0.01) in Th2, respectively.
CONCLUSIONS: Asthma and wheeze outcomes in children at 24 months of age are associated with elevated Th2 status in children at an early age. Our data further suggest that early exposures to an agricultural environment, breast-feeding, pets, and gas stoves affect the development of children's Th1/Th2 immune response.
KEY WORDS: allergen, breast-feeding, children, endotoxin, flow cytometry, interferon-[gamma], interleukin-4, organophosphate, pesticide, T-helper cytokines. Environ Health Perspect 114:1916-1922 (2006). doi:10.1289/ehp.9306 available via http://dx.doi.org/ [Online 17 August 2006]
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Pesticides are ubiquitous in the environment as a result of widespread agricultural and domestic use. Exposure to organophosphate (OP) pesticides has been linked in a small number of epidemiologic studies to asthma or asthma-related symptoms. In a study of pesticide applicators in Iowa and North Carolina, OP exposure in the preceding year was related to wheeze (Hoppin et al. 2002). Respiratory, asthma-like symptoms were associated with exposures to OPs in occupational and environmental settings among villagers in rural China (Zhang et al. 2002). Another recent study in Southern California of early-life risk factors for asthma reported that those children exposed to herbicides and pesticides in the first year of life had significantly elevated risks of developing asthma (Salam et al. 2004). Other studies (Ernst 2002; Kheradmand et al. 2002; Landau 2001; Peden 2000) have suggested a relationship between pesticide exposure and exacerbation and/or onset of childhood asthma, but a causal role remains to be established.
Children of migrant farmworkers who live in rural agricultural communities may be exposed to higher levels of pesticides than other children because of their proximity to fields and potential "take-home" exposures from their parents (Bradman et al. 2005; Eskenazi et al. 2004; Fenske et al. 2000; Harnly et al. 2005; Lambert et al. 2005). In addition to pesticides, children who reside in agricultural communities are also exposed to bacterial endotoxin and allergens (Braun-Fahrlander et al. 2002; Gereda et al. 2000). Exposure to endotoxin during early childhood is associated with decreased occurrence of hay fever, atopic asthma, and atopic sensitization in children (Braun-Fahrlander et al. 2002; Gehring et al. 2002; von Mutius et al. 2000), whereas early exposure to allergens, such as house dust mite Dermatophagoides pteronyssinus (Der p 1), is considered a risk factor for development of asthma in children (Ohshima et al. 2002; Peat et al. 1996; Sporik et al. 1990).
Asthma is characterized by chronic inflammation in the airways and the presence of a predominance of CD[4.sup.+] T-helper 2 (Th2) cells that secrete interleukin (IL)-4, IL-5, and IL-13 cytokines (Romagnani 1994). Th2 cells contribute to the immunopathogenesis of asthma by recruiting eosinophils and mast cells to the airways (de Vries et al. 2000; Kuo et al. 2001; Romagnani 1994) and by inducing B-cells to produce immunoglobulin E antibodies (Yssel et al. 1998). Conversely, T-helper 1 (Th1) cells that secrete interferon (IFN)-[gamma] are thought to protect against the development of asthma by regulating Th2 cytokine production, although a mixed Th1/Th2 pattern has been reported (Heaton et al. 2005). Allergic and asthmatic subjects are more likely to have elevated levels of the Th2 cytokines IL-4 and IL-5, and reduced levels of the Th1 cytokines IFN-[gamma] and tumor necrosis factor (TNF)-[beta] (Cohn et al. 2004; Romagnani 1994; Sanchez-Guerrero et al. 1997). However, increased levels of IFN-[gamma] also have been reported in cases of severe asthma that could involve CD[8.sup.+] T cells (Brown et al. 2003; Magnan et al. 2000).
The rapid uptake of Th1/Th2 cytokines by nearby immune cells requires that blood samples be analyzed soon after collection to account for cytokine absorption kinetics (Pala et al. 2000). This may be difficult in epidemiologic studies where samples are collected in the field and then transported to a laboratory for analysis. Therefore, to study the associations between Th1/Th2 cytokines and environmental exposures and the occurrence of asthma in children, we optimized a flow cytometry-based method of intracellular cytokine detection to analyze transported samples with minimal blood volumes (Duramad et al. 2004). IFN-[gamma] and IL-4 are signature cytokines of Th1 and Th2 cells, respectively (Pala et al. 2000). Because only memory cells would be able to synthesize IFN-[gamma] and IL-4 within the 4-hr stimulus period used in this study, this method allowed us to identify the cellular sources of the cytokines of interest. The aims of the present study were threefold: a) to use this method to characterize Th1 and Th2 cytokine profiles in a birth cohort of 12-and 24-month-old children residing in an agricultural community; b) to evaluate associations between early environmental exposures in the first year of life and children's cytokine profiles at 12 and 24 months of age; and c) to investigate the associations of these early-life cytokine profiles with the diagnosis of childhood asthma.
Materials and Methods
Participants and recruitment. The CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) project, a component of the Center for Children's Environmental Health Research at the University of California, Berkeley, is a longitudinal birth cohort study of the effects of pesticides and other environmental exposures on the health of pregnant women and their children who live in the Salinas Valley, Monterey County, California (Eskenazi et al. 2003). Several hundred thousand pounds of OP and pyrethroid pesticides are applied annually in this agricultural area (California Environmental Protection Agency 2002).
Pregnant women who entered prenatal care at the county hospital or one of five community clinics were screened for eligibility between October 1999 and October 2000. These facilities serve a low-income, largely Mexican farmworker population. Eligible women were [greater than or equal to] 18 years of age, < 20 weeks gestation at enrollment, spoke English or Spanish,...
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