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Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2024)

Background: The developing fetal brain and lungs are sensitive to many environmental exposures. However, the independent and joint effects of early pregnancy and early childhood exposure to metals and micronutrients on child cognition and respiratory function are not well-understood.

Objectives: Our aims were to estimate: (1) associations of first-trimester (~10 weeks) maternal erythrocyte concentrations of mixtures of non-essential and essential metals and micronutrients with early- (~3 years) and mid-childhood (~8 years) cognitive test scores in Project Viva, a pre-birth cohort in Boston, Massachusetts, USA; (2) associations of early childhood (~3 years of age) erythrocyte metal concentrations with cognitive test scores at early and mid-childhood (~8 years of age); and, (3) independent and joint associations of first-trimester (~10 weeks) erythrocyte concentrations of 11 essential and non-essential metals with mid-childhood (~8 years) lung function and asthma.

Methods: We measured concentrations of five essential metals (copper (Cu), magnesium (Mg), manganese (Mn), selenium (Se), zinc (Zn)), six non-essential metals (arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb)), and two micronutrients (vitamin B12 and folate), in first-trimester (~10 weeks) maternal blood. In early childhood (~3 years) blood, we assessed these metals as well as two additional essential metals, cobalt (Co) and molybdenum (Mo), and non-essential metals, tin (Sn) and strontium (Sr) . We assessed visual-motor function and receptive vocabulary in early childhood (~3 years), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (~8 years). Measures of lung function [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), ratio of FEV1 to FVC (FEV1/FVC), and forced expiratory flow from the 25th to 75th percentiles of FVC (FEF25-75))] were obtained by spirometry, and asthma status by recall, at the mid-childhood (~8 years) visit. We employed linear and logistic regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation, to evaluate individual and joint associations of the essential and non-essential metal mixtures with the outcomes. In analyses of lung function and asthma, we additionally fit Bayesian hierarchical models (BHMs) with informative priors. All models were adjusted for maternal and child sociodemographic and nutritional confounders.

Results: (1) First-trimester metals and cognition: Analyses included 900 mother-child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points (95% confidence interval (CI): 0.06, 3.10), driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of -3.01 points (95% CI: -5.55, -0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. (2) Early childhood metals and cognition: We analyzed 349 children (median whole blood Pb ~1 µg/dL). In cross-sectional analyses, each doubling of Pb was associated with lower visual-motor function (mean difference: -2.43 points, 95% confidence interval (CI): -4.01, -0.86) and receptive vocabulary, i.e., words understood (-1.45 points, 95% CI: -3.26, 0.36). Associations of Pb with mid-childhood cognition were weaker and less precise by comparison. Mg was positively associated with cognition in cross-sectional but not prospective analyses, and cross-sectional associations were attenuated in a sensitivity analysis removing adjustment for concurrent metals. We did not observe joint associations or interactions. (3) First-trimester metals, lung function, and asthma: The analytic sample included 804 mother-child pairs (76.0% non-Hispanic White; 16.7% currently asthmatic). Each standard deviation (SD) increase in Mg was associated with increases in FEV¬¬1 (mean difference: 26 mL, 95% credible interval (CrI): 7, 44) and FVC (27 mL, 95% CrI: 6, 48), but not FEV1/FVC. Each SD increase in Mg was associated with lower odds of current asthma (OR: 0.88, 95% CrI: 0.71, 1.09). Estimates from multiple linear and logistic regressions were larger in magnitude and less precise than those from BHMs, though conclusions were consistent between the methods. Joint increases in the essential metals or non-essential metals were not associated with lung function and asthma.

Discussion: In the first chapter, we found that maternal circulating concentrations of several essential (Zn and Se) and non-essential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. In the second chapter, we found that in this cohort with low blood Pb levels in early childhood, increased blood Pb was robustly associated with lower cognitive ability in cross-sectional analyses, even after adjustment for prenatal Pb exposure, and regardless of adjustment for metal co-exposures. However, associations with mid-childhood cognition were attenuated and imprecise, suggesting some buffering of Pb neurotoxicity in early life. Finally, results from the third chapter suggest early pregnancy intake of Mg may reduce restrictive respiratory patterns, and may confer a small reduction in the risk of asthma. BHMs provided more conservative and more precise estimates than traditional frequentist methods.

    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2022)
    Carriers of the cystic fibrosis transmembrane conductance regulator (CFTR) gene ("carriers") have been found to have an increased risk of persistent asthma. However, it is unclear at what level of CFTR function this risk exists and whether it is modified by asthmogens, such as air pollution. We conducted a retrospective cohort study of children born in California between July 2007 and December 2013, linking CFTR genotype data from the California newborn screening program to Medicaid claims records through March 17, 2020 to identify asthma cases, and to air pollution data from CalEnviroScreen 3.0 to identify levels of particulate matter with diameter 2.5 microns or smaller (PM2.5 ). Log-binomial regression models for asthma risk were fitted, adjusting for race/ethnicity and sex. Compared to population controls, carriers had higher risk of asthma (adjusted risk ratio (aRR) = 1.29, 95% confidence interval (CI): 0.98, 1.69; p < 0.1). Other non-CF-causing variants on the second allele did not appear to further increase risk. Genotypes with the greatest asthma risk were F508del with an intron 10 T7 or (TG)11T5 in trans (aRR=1.52, 95% CI: 1.10, 2.12). This association was higher among children living in areas at or above (aRR = 1.80) versus below (aRR = 1.37) the current national air quality standard for PM2.5 , though this difference was not statistically significant (pinteraction  > 0.2). These results suggest carriers with CFTR functional levels between 25% and 45% of wildtype are at increased risk of asthma. Knowledge of CFTR genotype in asthmatics may be important to open new CFTR-related treatment options for these patients.
      Cover page: CFTR gene variants, air pollution, and childhood asthma in a California Medicaid population
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2022)
      The Food and Drug Administration (FDA) regulates artificial food colors (AFCs) in the United States. Exposure to AFCs has raised concerns about adverse behavioral effects in children. We quantified AFC exposure in women of childbearing age, pregnant women, and children and compared them to FDA and World Health Organization acceptable daily intakes (ADIs). We estimated the “typical” and “high” single-day and two-day average dietary exposure to each AFC (mg/kg/day) based on laboratory measurements and food consumption data from the 2015−2016 National Health and Nutrition Examination Survey (NHANES). We also examined whether AFC intake differed by income, education, and ethnicity. Exposure tended to be higher in children and the highest AFC exposure was found for Red No. 40. Children’s mean and 95th percentile FD&C Red No. 3 estimated intakes exceeded the ADIs in some instances. Juice drinks, soft drinks, icings, and ice cream cones were major foods contributing to children’s (<16 years old) AFC exposure. AFC intake was higher in participants with lower incomes and education and of African American ethnicity. The findings indicate widespread AFC exposure including in very young children. Research is needed on the sociodemographic determinants of exposure and AFC toxicokinetics to better describe the absorption and organ-specific exposure.
        Cover page: Dietary Exposure to United States Food and Drug Administration-Approved Synthetic Food Colors in Children, Pregnant Women, and Women of Childbearing Age Living in the United States
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2023)
        BACKGROUND: Food and Drug Administration (FDA) Food Drug and Cosmetic (FD&C) synthetic color additives (SCAs) have been associated with attentional and behavioral problems in children. Efforts to quantify exposure have focused on foods, while the contribution of medications and supplements remains unknown. OBJECTIVE: To estimate exposures to SCAs in children (2-16 years) and pregnant women from intake of common over-the-counter (OTC) medications and vitamins. METHODS: We estimated single-day exposure (mg/kg/day) to FD&C SCAs based on measurements of 25 different products and recommended dosages on product labels. Exposures were compared to SCA exposure estimates from food we previously developed and acceptable daily intakes (ADIs) established by FDA and the World Health Organization. RESULTS: The highest exposure was found for FD&C Red No. 40 in a childrens cold/cough/allergy syrup. A child aged 12-16 years consuming the maximum daily dosage would have an exposure of 0.221 mg/kg/day, which is twice this age groups typical exposure to this additive from food. No estimated exposures exceeded the ADIs. SIGNIFICANCE: Some childrens OTC medications and vitamins may cause daily SCA exposures comparable to those from foods. OTC medications and vitamins should be considered in efforts to quantify population exposure to FD&C SCAs. IMPACT: Exposure to synthetic color additives (SCAs) from foods has been associated with behavioral problems in children. Exposures from over-the-counter (OTC) medications and vitamins remain unquantified despite widespread use. We estimated exposures in children and pregnant women for 25 different OTC medication and vitamin products sold in the United States. While exposures were below acceptable daily intakes (ADIs) established by the US Food and Drug Administration and the World Health Organization, some were comparable to typical daily exposures from foods. This work critically informs future SCA exposure assessments and provides valuable information for parents concerned about the health effects of SCAs.
          Cover page: Exposures to FD&amp;C synthetic color additives from over-the-counter medications and vitamins in United States children and pregnant women.
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2023)
          BACKGROUND: The developing fetal brain is sensitive to many environmental exposures. However, the independent and joint effects of prenatal exposure to metals and micronutrients on child cognition are not well understood. OBJECTIVES: Our aim was to evaluate associations of first-trimester (∼10 wk) maternal erythrocyte concentrations of mixtures of nonessential and essential metals and micronutrients with early (∼3 y) and mid-childhood (∼8 y) cognitive test scores in Project Viva, a prebirth cohort in Boston, Massachusetts, USA. METHODS: We measured concentrations of five essential metals (Cu, Mg, Mn, Se, Zn) and two micronutrients (vitamin B12 and folate), together termed the nutrient mixture, as well as six nonessential metals (As, Ba, Cd, Cs, Hg, Pb), together termed the neurotoxic mixture, in first-trimester (∼10 wk) maternal erythrocytes (metals) or plasma (micronutrients). We assessed visual-motor function and receptive vocabulary in early childhood (∼3 y), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (∼8 y). We employed adjusted quantile g-computation and linear regression to estimate mixture and individual component associations, respectively. RESULTS: Analyses included 900 mother-child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points [95% confidence interval (CI): 0.06, 3.10], driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of -3.01 points (95% CI: -5.55, -0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. DISCUSSION: Maternal circulating concentrations of several essential (Zn and Se) and nonessential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. https://doi.org/10.1289/EHP12016.
            Cover page: Mixtures of Metals and Micronutrients in Early Pregnancy and Cognition in Early and Mid-Childhood: Findings from the Project Viva Cohort.
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2023)

            Background

            Water, sanitation, and hygiene (WASH) improvements are promoted to reduce diarrhoea in low-income countries. However, trials from the past 5 years have found mixed effects of household-level and community-level WASH interventions on child health. Measuring pathogens and host-specific faecal markers in the environment can help investigate causal pathways between WASH and health by quantifying whether and by how much interventions reduce environmental exposure to enteric pathogens and faecal contamination from human and different animal sources. We aimed to assess the effects of WASH interventions on enteropathogens and microbial source tracking (MST) markers in environmental samples.

            Methods

            We did a systematic review and individual participant data meta-analysis, which included searches from Jan 1, 2000, to Jan 5, 2023, from PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus, of prospective studies with water, sanitation, or hygiene interventions and concurrent control group that measured pathogens or MST markers in environmental samples and measured child anthropometry, diarrhoea, or pathogen-specific infections. We used covariate-adjusted regression models with robust standard errors to estimate study-specific intervention effects and pooled effect estimates across studies using random-effects models.

            Findings

            Few trials have measured the effect of sanitation interventions on pathogens and MST markers in the environment and they mostly focused on onsite sanitation. We extracted individual participant data on nine environmental assessments from five eligible trials. Environmental sampling included drinking water, hand rinses, soil, and flies. Interventions were consistently associated with reduced pathogen detection in the environment but effect estimates in most individual studies could not be distinguished from chance. Pooled across studies, we found a small reduction in the prevalence of any pathogen in any sample type (pooled prevalence ratio [PR] 0·94 [95% CI 0·90-0·99]). Interventions had no effect on the prevalence of MST markers from humans (pooled PR 1·00 [95% CI 0·88-1·13]) or animals (pooled PR 1·00 [95% CI 0·97-1·03]).

            Interpretation

            The small effect of these sanitation interventions on pathogen detection and absence of effects on human or animal faecal markers are consistent with the small or null health effects previously reported in these trials. Our findings suggest that the basic sanitation interventions implemented in these studies did not contain human waste and did not adequately reduce exposure to enteropathogens in the environment.

            Funding

            Bill and Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office.
              Creative Commons 'BY' version 4.0 license
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2022)
              ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) AND ATXR6 are required for the deposition of H3K27me1 and for maintaining genomic stability in Arabidopsis Reduction of ATXR5/6 activity results in activation of DNA damage response genes, along with tissue-specific derepression of transposable elements (TEs), chromocenter decompaction, and genomic instability characterized by accumulation of excess DNA from heterochromatin. How loss of ATXR5/6 and H3K27me1 leads to these phenotypes remains unclear. Here we provide extensive characterization of the atxr5/6 hypomorphic mutant by comprehensively examining gene expression and epigenetic changes in the mutant. We found that the tissue-specific phenotypes of TE derepression and excessive DNA in this atxr5/6 mutant correlated with residual ATXR6 expression from the hypomorphic ATXR6 allele. However, up-regulation of DNA damage genes occurred regardless of ATXR6 levels and thus appears to be a separable process. We also isolated an atxr6-null allele which showed that ATXR5 and ATXR6 are required for female germline development. Finally, we characterize three previously reported suppressors of the hypomorphic atxr5/6 mutant and show that these rescue atxr5/6 via distinct mechanisms, two of which involve increasing H3K27me1 levels.
                Cover page: The role of ATXR6 expression in modulating genome stability and transposable element repression in Arabidopsis
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