RESUMEN

BACKGROUND: The incidence of testicular germ cell tumors (TGCT) is increasing steadily in the United States, particularly among Latinos. TGCT is thought to be initiated in utero and exposure to endocrine-disrupting chemicals, suspected contributors to TGCT pathogenesis, during this critical developmental period may contribute to the rise. OBJECTIVES: To assess the relationship between fetal exposure to agricultural endocrine-disrupting pesticides (EDPs) and TGCT risk among adolescents in a diverse population in California. METHODS: We conducted a registry-based case-control study of TGCT. Cases, diagnosed between 1997 and 2011, were 15-19 years of age (n = 381). Controls were matched on birth year and race/ethnicity (n = 762). Quantities (kilograms) of 33 pesticides applied within 3 km and 1 km radii of each individual's address before birth were estimated using the Pesticide Use Reporting database. Odds ratios (OR), 95% confidence intervals (CI), and population attributable risk (PAR) were calculated for each EDP (using log-2 transformed values). Risk models considered race/ethnicity, birth year, and neighborhood socioeconomic status. RESULTS: A doubling of nearby acephate applications (3 km and 1 km radii) and malathion applications (1 km radius) was associated with increased risks of TGCT among Latinos only (OR = 1.09; 95% CI:1.01-1.17; 1.30; 95% CI:1.08-1.57, and 1.19; 95% CI:1.01-1.39, respectively), whereas application of carbaryl within a 3 km radius increased TGCT risk in non-Latinos only (OR = 1.14, 95% CI:1.01-1.28). We estimate that acephate was associated with approximately 10% of the TGCT PAR, malathion with 3% and carbaryl with 1%. CONCLUSIONS: TGCT among adolescents in California was associated with prenatal residential proximity to acephate and malathion among Latinos, and with carbaryl among non-Latinos. These results suggest that the rise in TGCT risk among Latinos may be associated with exposure to these pesticides.

Asunto(s)

Neoplasias de Células Germinales y Embrionarias , Plaguicidas , Adolescente , California/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/epidemiología , Embarazo , Factores de Riesgo , Neoplasias Testiculares , Estados Unidos

RESUMEN

BACKGROUND: Self-reported residential use of pesticides has consistently been associated with increased risk of childhood leukemia. However, these studies were limited in their ability to identify specific insecticide active ingredients that were associated with risk. OBJECTIVE: We used household carpet dust measurements of 20 insecticides (two carbamate, 10 organophosphate, two organochlorine, and six pyrethroid) as indicators of exposure and evaluated associations with the risk of childhood acute lymphoblastic leukemia (ALL). METHODS: We conducted a population-based case-control study of 252 ALL cases diagnosed from 1999 to 2007 and 306 birth certificate controls from 35 counties in Central and Northern California. Carpet dust was collected at a second interview (2001-2007) for cases who had not moved since diagnosis (comparable reference date for controls) using a specialized vacuum cleaner in the room where the child spent most of their time or from the household vacuum. Insecticides were categorized as detected (yes/no), or as tertiles or quartiles of their distributions among controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression adjusting for demographic characteristics, interview year, and season of dust collection. RESULTS: Permethrin, chlorpyrifos, diazinon, and carbaryl were the most frequently detected insecticide active ingredients. When we compared the highest quartile to the lowest or to non-detections, there was no association with ALL for permethrin (OR Q4 vs. Q1 = 0.81; 95% CI 0.50-1.31), carbaryl (OR Q4 vs. non-detects = 0.61, 95% CI 0.34-1.08) or chlorpyrifos (OR Q4 vs. Q1 = 0.60; 95% CI 0.36-1.00). The highest quartile of diazinon concentration was inversely associated with risk in the single pesticide model but without a monotonic exposure-response (p-trend = 0.14). After adjusting for other common insecticides, the OR was not significant (OR Q4 vs. Q1 = 0.58; 95% CI 0.33-1.05). None of the other insecticides were associated with risk. CONCLUSION: Our results should be interpreted within the limitations of the case-control study design including the use of a single post-diagnosis dust sample and restriction to residentially stable participants, which may have resulted in selection bias. Although difficult to implement, additional studies with assessment of exposure to insecticide active and non-active ingredients are necessary to elucidate the role of these common exposures in childhood leukemia risk.

Asunto(s)

Cloropirifos , Insecticidas , Plaguicidas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piretrinas , Carbamatos/toxicidad , Estudios de Casos y Controles , Polvo/análisis , Exposición a Riesgos Ambientales/análisis , Humanos , Insecticidas/toxicidad , Plaguicidas/análisis , Leucemia-Linfoma Linfoblástico de Células Precursoras/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Piretrinas/toxicidad

RESUMEN

BACKGROUND: Prenatal immune development may play an important role in the etiology of childhood acute lymphoblastic leukemia (ALL). METHODS: Seven cytokines, IL1ß, IL4, IL6, IL8, GM-CSF, TNFα, and VEGF, were analyzed in blood spots collected at birth from 1,020 ALL cases and 1,003 controls participating in the California Childhood Leukemia Study. ORs and 95% confidence intervals (95% CI) associated with an interquartile range increment in cytokine levels were calculated using logistic regression, adjusting for sociodemographic and birth characteristics. RESULTS: We found that patients with ALL were born with higher levels of a group of correlated cytokines than controls [IL1ß: OR of 1.18 (95% confidence interval [CI], 1.03-1.35); IL8: 1.19 (1.03-1.38); TNFα: 1.15 (1.01-1.30); VEGF: 1.16 (1.01-1.33)], especially among children of Latina mothers (ORs from 1.31 to 1.40) and for ALL with high hyperdiploidy (ORs as high as 1.27). We found that neonatal cytokine levels were correlated with neonatal levels of endogenous metabolites which had been previously associated with ALL risk; however, there was no evidence that the cytokines were mediating the relationship between these metabolites and ALL risk. CONCLUSIONS: We posit that children born with altered cytokine levels are set on a trajectory towards an increased risk for subsequent aberrant immune reactions that can initiate ALL. IMPACT: This is the first study to evaluate the interplay between levels of immunomodulatory cytokines at birth, prenatal exposures, and the risk of childhood ALL.

Asunto(s)

Citocinas/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Biomarcadores/sangre , California/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Factores de Riesgo

RESUMEN

BACKGROUND: Parental smoking is implicated in the etiology of acute lymphoblastic leukemia (ALL), the most common childhood cancer. We recently reported an association between an epigenetic biomarker of early-life tobacco smoke exposure at the AHRR gene and increased frequency of somatic gene deletions among ALL cases. METHODS: Here, we further assess this association using two epigenetic biomarkers for maternal smoking during pregnancy-DNA methylation at AHRR CpG cg05575921 and a recently established polyepigenetic smoking score-in an expanded set of 482 B-cell ALL (B-ALL) cases in the California Childhood Leukemia Study with available Illumina 450K or MethylationEPIC array data. Multivariable Poisson regression models were used to test the associations between the epigenetic biomarkers and gene deletion numbers. RESULTS: We found an association between DNA methylation at AHRR CpG cg05575921 and deletion number among 284 childhood B-ALL cases with MethylationEPIC array data, with a ratio of means (RM) of 1.31 [95% confidence interval (CI), 1.02-1.69] for each 0.1 ß value reduction in DNA methylation, an effect size similar to our previous report in an independent set of 198 B-ALL cases with 450K array data [meta-analysis summary RM (sRM) = 1.32; 95% CI, 1.10-1.57]. The polyepigenetic smoking score was positively associated with gene deletion frequency among all 482 B-ALL cases (sRM = 1.31 for each 4-unit increase in score; 95% CI, 1.09-1.57). CONCLUSIONS: We provide further evidence that prenatal tobacco-smoke exposure may influence the generation of somatic copy-number deletions in childhood B-ALL. IMPACT: Analyses of deletion breakpoint sequences are required to further understand the mutagenic effects of tobacco smoke in childhood ALL.

Asunto(s)

Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Epigénesis Genética , Eliminación de Gen , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Efectos Tardíos de la Exposición Prenatal , Proteínas Represoras/genética , Contaminación por Humo de Tabaco/efectos adversos , Adulto , Preescolar , Islas de CpG , Metilación de ADN , Femenino , Humanos , Embarazo

RESUMEN

The etiology of pediatric acute myeloid leukemia (AML) is largely unknown, but evidence for mutations in utero and long latency periods suggests that environmental factors play a role. Therefore, we used untargeted metabolomics of archived newborn dried blood spots (DBS) to investigate neonatal exposures as potential causal risk factors for AML. Untargeted metabolomics profiling was performed on DBS punches from 48 pediatric patients with AML and 46 healthy controls as part of the California Childhood Leukemia Study (CCLS). Because sex disparities are suggested by differences in AML incidence rates, metabolite features associated with AML were identified in analyses stratified by sex. There was no overlap between the 16 predictors of AML in females and 15 predictors in males, suggesting that neonatal metabolomic profiles of pediatric AML risk are sex-specific. In females, four predictors of AML were putatively annotated as ceramides, a class of metabolites that has been linked with cancer cell proliferation. In females, two metabolite predictors of AML were strongly correlated with breastfeeding duration, indicating a possible biological link between this putative protective risk factor and childhood leukemia. In males, a heterogeneous metabolite profile of AML predictors was observed. Replication with larger participant numbers is required to validate findings.

Asunto(s)

Pruebas con Sangre Seca , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Metabolómica , Biología Computacional/métodos , Pruebas con Sangre Seca/métodos , Femenino , Humanos , Recién Nacido , Leucemia Mieloide Aguda/etiología , Masculino , Metaboloma , Metabolómica/métodos , Pronóstico , Factores Sexuales

RESUMEN

There has been a growing interest in the literature on multiple environmental risk factors for diseases and an increasing emphasis on assessing multiple environmental exposures simultaneously in epidemiologic studies of cancer. One method used to analyze exposure to multiple chemical exposures is weighted quantile sum (WQS) regression. While WQS regression has been demonstrated to have good sensitivity and specificity when identifying important exposures, it has limitations including a two-step model fitting process that decreases power and model stability and a requirement that all exposures in the weighted index have associations in the same direction with the outcome, which is not realistic when chemicals in different classes have different directions and magnitude of association with a health outcome. Grouped WQS (GWQS) was proposed to allow for multiple groups of chemicals in the model where different magnitude and direction of associations are possible for each group. However, GWQS shares the limitation of WQS of a two-step estimation process and splitting of data into training and validation sets. In this paper, we propose a Bayesian group index model to avoid the estimation limitation of GWQS while having multiple exposure indices in the model. To evaluate the performance of the Bayesian group index model, we conducted a simulation study with several different exposure scenarios. We also applied the Bayesian group index method to analyze childhood leukemia risk in the California Childhood Leukemia Study (CCLS). The results showed that the Bayesian group index model had slightly better power for exposure effects and specificity and sensitivity in identifying important chemical exposure components compared with the existing frequentist method, particularly for small sample sizes. In the application to the CCLS, we found a significant negative association for insecticides, with the most important chemical being carbaryl. In addition, for children who were born and raised in the home where dust samples were taken, there was a significant positive association for herbicides with dacthal being the most important exposure. In conclusion, our approach of the Bayesian group index model appears able to make a substantial contribution to the field of environmental epidemiology.

Asunto(s)

Contaminantes Ambientales , Neoplasias , Teorema de Bayes , Niño , Polvo , Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/toxicidad , Humanos , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Proyectos de Investigación

RESUMEN

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.

Asunto(s)

Sistema Inmunológico/efectos de los fármacos , Leucemia/etiología , Linfoma/etiología , Nicotiana/efectos adversos , Humo/efectos adversos , Animales , Leucemia/inmunología , Linfoma/inmunología , Ratones Transgénicos , Contaminación por Humo de Tabaco/efectos adversos , Contaminación por Humo de Tabaco/análisis

RESUMEN

Individuals are exposed to a large number of diverse environmental chemicals simultaneously and the evaluation of multiple chemical exposures is important for identifying cancer risk factors. The measurement of a large number of chemicals (the exposome) in epidemiologic studies is allowing for a more comprehensive assessment of cancer risk factors than was done in earlier studies that focused on only a few chemicals. Empirical evidence from epidemiologic studies shows that chemicals from different chemical classes have different magnitudes and directions of association with cancers. Given increasing data availability, there is a need for the development and assessment of statistical methods to model environmental cancer risk that considers a large number of diverse chemicals with different effects for different chemical classes. The method of grouped weighted quantile sum (GWQS) regression allows for multiple groups of chemicals to be considered in the model such that different magnitudes and directions of associations are possible for each group of chemicals. In this paper, we assessed the ability of GWQS regression to estimate exposure effects for multiple chemical groups and correctly identify important chemicals in each group using a simulation study. We compared the performance of GWQS regression with WQS regression, the least absolute shrinkage and selection operator (lasso), and the group lasso in estimating exposure effects and identifying important chemicals. The simulation study results demonstrate that GWQS is an effective method for modeling exposure to multiple groups of chemicals and compares favorably with other methods used in mixture analysis. As an application, we used GWQS regression in the California Childhood Leukemia Study (CCLS), a population-based case-control study of childhood leukemia in California to estimate exposure effects for many chemical classes while also adjusting for demographic factors. The CCLS analysis found evidence of a positive association between exposure to the herbicide dacthal and an increased risk of childhood leukemia.

Asunto(s)

Exposición a Riesgos Ambientales , Neoplasias , Estudios de Casos y Controles , Niño , Simulación por Computador , Exposición a Riesgos Ambientales/análisis , Humanos , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Proyectos de Investigación , Medición de Riesgo , Factores de Riesgo

RESUMEN

The developing fetus is exposed to chemicals, which are metabolized to electrophiles that form adducts with nucleophilic Cys34 of human serum albumin (HSA). By measuring these adducts in neonatal blood spots (NBS), we obtain information regarding fetal exposures during the last month of gestation. To discover potential risk factors for childhood leukemia resulting from in utero exposures, we used untargeted adductomics to measure HSA-Cys34 adducts in 782 archived NBS, collected from incident cases of childhood acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) and matched population-based controls. Among a total of 28 Cys34 modifications that were measured, we found no differences in adduct abundances between childhood leukemia cases and controls overall. However, cases of T-cell ALL had higher abundances of adducts of reactive carbonyl species and a Cys34 disulfide of homocysteine was present at lower levels in AML cases. These results suggest that oxidative stress and lipid peroxidation may be etiologic factors of T-cell ALL, and alterations in one-carbon metabolism and epigenetic changes may be predictors of AML. Future replication of the results with larger sample sizes is necessary.

Asunto(s)

Pruebas con Sangre Seca , Leucemia/diagnóstico , Tamizaje Neonatal/métodos , Proteómica/métodos , Especies Reactivas de Oxígeno/análisis , Albúmina Sérica Humana/análisis , Adolescente , Edad de Inicio , Estudios de Casos y Controles , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Pruebas con Sangre Seca/métodos , Femenino , Humanos , Lactante , Recién Nacido , Leucemia/sangre , Leucemia/epidemiología , Peroxidación de Lípido , Masculino , Estrés Oxidativo/fisiología , Procesamiento Proteico-Postraduccional , Especies Reactivas de Oxígeno/sangre , Albúmina Sérica Humana/metabolismo

RESUMEN

E-cigarette use is increasing dramatically among adolescents as social media marketing portrays "vaping" products as healthier alternatives to conventional cigarettes. In September 2018, the Food and Drug Administration (FDA) launched an anti-vaping campaign, in U.S. high schools, on social media and other platforms, emphasizing "The Real Cost" of e-cigarettes. Using a novel deep learning approach, we assessed changes in vaping-related content on Instagram from 2017 to 2019 and drew an inference about the initial impact of the FDA's Real Cost campaign on Instagram. We collected 245,894 Instagram posts that used vaping-related hashtags (e.g., #vape, #ejuice) in four samples from 2017 to 2019. We compared the "like" count from these posts before and after the FDA campaign. We used deep learning image classification to analyze 49,655 Instagram image posts, separating images of men, women, and vaping devices. We also conducted text analysis and topic modeling to detect the common words and themes in the posted captions. Since September 2018, the FDA-sponsored hashtag #TheRealCost has been used about 50 times per month on Instagram, whereas vaping-related hashtags we tracked were used up to 10,000 times more often. Comparing the pre-intervention (2017, 2018) and post-intervention (2019) samples of vaping-related Instagram posts, we found a three-fold increase in the median "like" count (10 vs. 28) and a 6-fold increase in the proportion of posts with more than 100 likes (2 vs. 15%). Over 70% of Instagram vaping images featured e-juices and devices, with a growing number of images depicting a "pod," the type of discrete vaping device that delivers high concentration of nicotine and is favored by novice e-cigarette users. In addition, the Instagram analytics data shared by the vaping influencers we interviewed showed underage Instagram users among their followers.

Asunto(s)

Síndrome de Down/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , California/epidemiología , California/etnología , Estudios de Casos y Controles , Niño , Preescolar , Cromosomas Humanos Par 21/genética , Síndrome de Down/complicaciones , Síndrome de Down/etnología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Guatemala/epidemiología , Guatemala/etnología , Haplotipos , Hispánicos o Latinos , Humanos , Lactante , Recién Nacido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnología , Análisis de Componente Principal , Factores de Riesgo , Regulador Transcripcional ERG/genética

RESUMEN

BACKGROUND: Untargeted metabolomics datasets contain large proportions of uninformative features that can impede subsequent statistical analysis such as biomarker discovery and metabolic pathway analysis. Thus, there is a need for versatile and data-adaptive methods for filtering data prior to investigating the underlying biological phenomena. Here, we propose a data-adaptive pipeline for filtering metabolomics data that are generated by liquid chromatography-mass spectrometry (LC-MS) platforms. Our data-adaptive pipeline includes novel methods for filtering features based on blank samples, proportions of missing values, and estimated intra-class correlation coefficients. RESULTS: Using metabolomics datasets that were generated in our laboratory from samples of human blood, as well as two public LC-MS datasets, we compared our data-adaptive filtering method with traditional methods that rely on non-method specific thresholds. The data-adaptive approach outperformed traditional approaches in terms of removing noisy features and retaining high quality, biologically informative ones. The R code for running the data-adaptive filtering method is provided at https://github.com/courtneyschiffman/Metabolomics-Filtering . CONCLUSIONS: Our proposed data-adaptive filtering pipeline is intuitive and effectively removes uninformative features from untargeted metabolomics datasets. It is particularly relevant for interrogation of biological phenomena in data derived from complex matrices associated with biospecimens.

Asunto(s)

Metabolómica/métodos , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida , Neoplasias Colorrectales/metabolismo , Bases de Datos como Asunto , Humanos , Redes y Vías Metabólicas

RESUMEN

Early-life exposures are believed to influence the incidence of pediatric acute lymphoblastic leukemia (ALL). Archived neonatal blood spots (NBS), collected within the first days of life, offer a means to investigate small molecules that reflect early-life exposures. Using untargeted metabolomics, we compared abundances of small-molecule features in extracts of NBS punches from 332 children that later developed ALL and 324 healthy controls. Subjects were stratified by early (1-5 y) and late (6-14 y) diagnosis. Mutually-exclusive sets of metabolic features - representing putative lipids and fatty acids - were associated with ALL, including 9 and 19 metabolites in the early- and late-diagnosis groups, respectively. In the late-diagnosis group, a prominent cluster of features with apparent 18:2 fatty-acid chains suggested that newborn exposure to the essential nutrient, linoleic acid, increased ALL risk. Interestingly, abundances of these putative 18:2 lipids were greater in infants who were fed formula rather than breast milk (colostrum) and increased with the mother's pre-pregnancy body mass index. These results suggest possible etiologic roles of newborn nutrition in late-diagnosis ALL.

Asunto(s)

Pruebas con Sangre Seca , Metabolismo Energético , Fenómenos Fisiológicos Nutricionales del Lactante , Lípidos/sangre , Metabolómica , Tamizaje Neonatal/métodos , Estado Nutricional , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Adolescente , Factores de Edad , Biomarcadores/sangre , Alimentación con Biberón , Lactancia Materna , California/epidemiología , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Fórmulas Infantiles , Recién Nacido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevención & control , Factores Protectores , Medición de Riesgo , Factores de Riesgo

RESUMEN

Metabolism of chemicals from the diet, exposures to xenobiotics, the microbiome, and lifestyle factors (e.g., smoking, alcohol intake) produce electrophiles that react with nucleophilic sites in circulating proteins, notably Cys34 of human serum albumin (HSA). To discover potential risk factors resulting from in utero exposures, we are investigating HSA-Cys34 adducts in archived newborn dried blood spots (DBS) that reflect systemic exposures during the last month of gestation. The workflow includes extraction of proteins from DBS, measurement of hemoglobin (Hb) to normalize for blood volume, addition of methanol to enrich HSA by precipitation of Hb and other interfering proteins, digestion with trypsin, and detection of HSA-Cys34 adducts via nanoflow liquid chromatography-high-resolution mass spectrometry. As proof-of-principle, we applied the method to 49 archived DBS collected from newborns whose mothers either actively smoked during pregnancy or were nonsmokers. Twenty-six HSA-Cys34 adducts were detected, including Cys34 oxidation products, mixed disulfides with low molecular weight thiols (e.g., cysteine, homocysteine, glutathione, cysteinylglycine), and other modifications. Data were normalized with a novel method ("scone") to remove unwanted technical variation arising from HSA digestion, blood volume, DBS age, mass spectrometry analysis, and batch effects. Using an ensemble of linear and nonlinear models, the Cys34 adduct of cyanide was found to consistently discriminate between newborns of smoking and nonsmoking mothers with a mean fold change (smoking/nonsmoking) of 1.31. These results indicate that DBS adductomics is suitable for investigating in utero exposures to reactive chemicals and metabolites that may influence disease risks later in life.

Asunto(s)

Cisteína/análisis , Pruebas con Sangre Seca/métodos , Albúmina Sérica Humana/química , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Recién Nacido , Exposición Materna/efectos adversos , Oxidación-Reducción , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Fumar/efectos adversos , Fumar/sangre

RESUMEN

Background: Allergic disease is suspected to play a role in the development of childhood acute lymphoblastic leukemia (ALL). Studies conducted over the last several decades have yielded mixed results.Methods: We examined the association between allergy, a common immune-mediated disorder, and ALL in the California Childhood Leukemia Study (CCLS), a case-control study of 977 children diagnosed with ALL and 1,037 matched controls (1995-2015). History of allergies in the first year of life was obtained from interviews, mainly reported by mothers. Logistic regression analyses were conducted to estimate ORs and 95% confidence intervals (CIs), controlling for birth order, daycare attendance, and mode of delivery. In addition, we conducted meta-analyses with data from the CCLS and 12 published studies and employed a new method to estimate between-study heterogeneity (R_b).Results: Overall, no associations were observed between childhood ALL risk and specific allergy phenotypes or any allergy, as a group. However, having any allergy was associated with an increased risk of ALL among the youngest study participants. In the meta-analysis random-effects models, reduced odds of ALL were associated with hay fever (metaOR = 0.65; 95% CI, 0.47-0.90); however, restricting the analysis to studies that used medical records for assessment of allergy or recently published studies led to null or attenuated results.Conclusions: Overall, our findings do not support a clear association between allergy and childhood ALL.Impact: The degree to which epidemiologic studies can inform the relationship between allergies and risk of childhood ALL is limited by R_b. Cancer Epidemiol Biomarkers Prev; 27(10); 1142-50. ©2018 AACR.

Asunto(s)

Hipersensibilidad/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Estudios de Casos y Controles , Niño , Humanos , Pronóstico , Factores de Riesgo

RESUMEN

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (pmeta < 10-10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (pmeta = 2.1 x 10-10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10-5 ) and p300 (p = 1.55 x 10-3 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (pmeta = 1.3 x 10-15 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.

Asunto(s)

Cromosomas Humanos Par 10/genética , Estudio de Asociación del Genoma Completo/métodos , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Complejo Represivo Polycomb 1/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , California/etnología , Proteínas de Ciclo Celular/metabolismo , Niño , Mapeo Cromosómico , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Elementos de Facilitación Genéticos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Células K562 , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnología , Transactivadores/metabolismo , Adulto Joven

RESUMEN

Firefighters are exposed to chemicals during fire events and we previously demonstrated that fire station dust has high levels of polybrominated diphenyl ethers (PBDEs). In conducting the Fire Station Dust Study, we sought to further characterize the chemicals to which firefighters could be exposed - measuring the emerging class of phosphorous-containing flame retardants (PFRs) in fire stations, for the first time, as well as PBDEs. Dust samples from 26 fire stations in five states were collected from vacuum-cleaner bags and analyzed for PFRs and PBDEs. PFR concentrations were found to be on the same order of magnitude as PBDE concentrations (maximum PFR: 218,000ng/g; maximum PBDE: 351,000ng/g). Median concentrations of tri-n-butyl phosphate (TNBP), tris (2-chloroisopropyl) phosphate (TCIPP), and tris(1,3-dichloroisopropyl)phosphate (TDCIPP) in dust from fire stations were higher than those previously reported in homes and other occupational settings around the world. Total PFR levels did not vary significantly among states. Levels of TDCIPP were higher in stations where vacuum cleaners were used to clean surfaces other than the floor. PBDE levels were comparable to those found in our previous study of 20 California fire stations and much higher than levels in California residences. PFR and PBDE levels in fire station dust are higher than in other occupational and residential settings, underscoring the need to identify and control sources of this contamination.

Asunto(s)

Polvo/análisis , Contaminantes Ambientales/análisis , Retardadores de Llama/análisis , Organofosfatos/análisis , Bomberos , Humanos

RESUMEN

PURPOSE: We investigated the relationship between the risk of childhood leukemia and home remodeling, a surrogate for indoor chemical exposures. METHODS: We collected information on remodeling activities carried out between birth and diagnosis in homes of 609 acute lymphoblastic leukemia (ALL) cases, 89 acute myeloid leukemia (AML) cases, and 893 matched controls participating in the California Childhood Leukemia Study (1995-2008). We used multivariable logistic regression to estimate the risk of ALL and AML associated with six remodeling activities: construction, painting, recarpeting, reflooring, roofing, and weatherproofing. Models were adjusted for age, sex, Hispanic ethnicity, race, household annual income, and residential mobility. RESULTS: Construction in the home between birth and diagnosis was associated with a significant increase in ALL risk (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.14-2.02) and a nonsignificant increase in AML risk (OR: 1.75, 95% CI: 0.98-3.15). No other remodeling activities were associated with ALL or AML risk in the main analysis. When stratifying by Hispanic ethnicity, a positive relationship between ALL risk and painting was evident in Hispanic children (OR: 1.47, 95% CI: 1.04-2.07). CONCLUSIONS: Specific home remodeling activities appeared to be associated with increased risk of childhood ALL.

Asunto(s)

Contaminación del Aire Interior/efectos adversos , Contaminación del Aire Interior/estadística & datos numéricos , Materiales de Construcción/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Leucemia Mieloide Aguda/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Adolescente , California , Estudios de Casos y Controles , Niño , Preescolar , Etnicidad/estadística & datos numéricos , Femenino , Humanos , Lactante , Modelos Logísticos , Masculino , Oportunidad Relativa , Factores de Riesgo

RESUMEN

Thirdhand smoke (THS) is the contamination that persists after secondhand tobacco smoke has been emitted into air. It refers to the tobacco-related gases and particles that become embedded in materials, such as the carpet, walls, furniture, blankets, and toys. THS is not strictly smoke, but chemicals that adhere to surfaces from which they can be released back into the air, undergo chemical transformations and/or accumulate. Currently, the hazards of THS are not as well documented as the hazards of secondhand smoke (SHS). In this Perspective, we describe the distribution and chemical changes that occur as SHS is transformed into THS, studies of environmental contamination by THS, human exposure studies, toxicology studies using animal models and in vitro systems, possible approaches for avoiding exposure, remediation of THS contamination, and priorities for further research.

Asunto(s)

Contaminación del Aire Interior/análisis , Nicotiana , Humo , Animales , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Humanos , Material Particulado/análisis , Material Particulado/toxicidad

RESUMEN

INTRODUCTION: For pediatric diseases like childhood leukemia, a short latency period points to in-utero exposures as potentially important risk factors. Untargeted metabolomics of small molecules in archived newborn dried blood spots (DBS) offers an avenue for discovering early-life exposures that contribute to disease risks. OBJECTIVES: The purpose of this study was to develop a quantitative method for untargeted analysis of archived newborn DBS for use in an epidemiological study (California Childhood Leukemia Study, CCLS). METHODS: Using experimental DBS from the blood of an adult volunteer, we optimized extraction of small molecules and integrated measurement of potassium as a proxy for blood hematocrit. We then applied this extraction method to 4.7-mm punches from 106 control DBS samples from the CCLS. Sample extracts were analyzed with liquid chromatography high resolution mass spectrometry (LC-HRMS) and an untargeted workflow was used to screen for metabolites that discriminate population characteristics such as sex, ethnicity, and birth weight. RESULTS: Thousands of small molecules were measured in extracts of archived DBS. Normalizing for potassium levels removed variability related to varying hematocrit across DBS punches. Of the roughly 1,000 prevalent small molecules that were tested, multivariate linear regression detected significant associations with ethnicity (3 metabolites) and birth weight (15 metabolites) after adjusting for multiple testing. CONCLUSIONS: This untargeted workflow can be used for analysis of small molecules in archived DBS to discover novel biomarkers, to provide insights into the initiation and progression of diseases, and to provide guidance for disease prevention.