Maternal anemia and the risk of childhood cancer: A population-based cohort study in Taiwan.

BACKGROUND: Childhood cancer may be related to maternal health in pregnancy. Maternal anemia is a common condition in pregnancy, especially in low-income countries, but the association between maternal anemia and childhood cancer has not been widely studied. OBJECTIVE: To examine the potential relation between maternal anemia during pregnancy and childhood cancers in a population-based cohort study in Taiwan. METHODS: We examined the relationship between maternal anemia and childhood cancer in Taiwan (N = 2160 cancer cases, 2,076,877 noncases). Cases were taken from the National Cancer Registry, and noncases were selected from birth records. Using national health registries, we obtained maternal anemia diagnoses. We estimated the risks for childhood cancers using Cox proportional hazard analysis. RESULTS: There was an increased risk of cancers in children born to mothers with nutritional anemia (hazard ratio (HR): 1.32, 95% CI 0.99, 1.76). Iron deficiency anemia (HR: 1.30, 95% CI 0.97-1.75) carried an increased risk, while non-nutritional anemias were not associated with childhood cancer risk. CONCLUSION: Our results provide additional support for screening for anemia during pregnancy. Adequate nutrition and vitamin supplementation may help to prevent some childhood cancer.

Maternal anemia and childhood cancer: a population-based case-control study in Denmark.

BACKGROUND: Childhood cancer risk is associated with maternal health during pregnancy. Anemia in pregnancy is a common condition, especially in low-income countries, but a possible association between maternal anemia and childhood cancer has not been widely studied. METHODS: We examined the relation in a population-based study in Denmark (N = 6420 cancer cases, 160,485 controls). Cases were taken from the Danish Cancer Registry, and controls were selected from national records. We obtained maternal anemia diagnoses from the National Patient and Medical Births registries. In a separate analysis within the years available (births 1995-2014), we examined cancer risks among mothers taking prescribed vitamin supplements, using data from the National Prescription Register. We estimated the risks of childhood cancer using conditional logistic regression. RESULTS: The risks of neuroblastoma [odds ratio (OR= 1.83, 95% confidence interval (CI): 1.04, 3.22] and acute lymphoblastic leukemia (OR= 1.46, 95% CI 1.09, 1.97) were increased in children born to mothers with anemia in pregnancy. There was a two-fold increased risk for bone tumors (OR= 2.59, 95% CI: 1.42, 4.72), particularly osteosarcoma (OR= 3.54, 95% CI 1.60, 7.82). With regards to prescribed supplement use, mothers prescribed supplements for B12 and folate deficiency anemia (OR= 4.03, 95% CI 1.91, 8.50) had an increased risk for cancer in offspring. CONCLUSION: Our results suggest that screening for anemia in pregnancy and vitamin supplementation may be an actionable strategy to prevent some cases of childhood cancer.

Hexachlorocyclohexane exposure alters the microbiome of colostrum in Chinese breastfeeding mothers.

Breast milk, especially colostrum, is not just a source of nutrients and immune factors for the newborn, but also accumulates environmental persistent pollutants and its diverse microbes affect the early colonization of the newborn's gut. Little is known about associations between environmental pollutants and the microbial composition of human colostrum. We assessed the influence of hexachlorocyclohexane (HCH), a persistent organic pollutant (POP), in colostrums on the microbial composition of human colostrum samples. HCH concentrations in 89 colostrum samples collected from a population living on the easternmost island of China were measured via gas chromatography equipped with mass spectrometer (GC-MS), HCH exposure risks for infants via dietary intake of breast milk were assessed, and for 29 colostrum samples the microbiota were profiled using 16S rRNA gene pyrosequencing to assess the association with HCH exposure levels. Our study confirmed high colostrum exposure levels of total HCHs (12.19 ±â€¯13.68 µg L-1) in this Chinese population. We predominantly identified Proteobacteria (67.6%) and Firmicutes (25.1%) in colostrum and microbial diversity at the genus level differed between samples with different HCH levels; e.g., Pseudomonas which contains several HCH degrading strains was found in significantly higher abundance in γ-HCH rich samples. Also, microbes that were statistically significantly associated with HCH levels were also highly correlated with each other (false discovery rate (FDR)＜0.01) and clustered in network analysis. Microbial diversity is associated with HCH levels in human colostrum and these associations might be attributable to their HCH degrading ability. These finding provide first insights into the role that environmental persistent pollutants may play in the microbial composition of human colostrum and the colonization of the infant gut.

The association between lifestyle factors and Parkinson's disease progression and mortality.

BACKGROUND: Lifestyle factors may contribute to the development of Parkinson's disease, but little is known about factors that influence progression. The objective of the current study was to examine whether caffeine or alcohol consumption, physical activity, or cigarette smoking is associated with progression and survival among PD patients. METHODS: We assessed lifelong coffee, tea, and alcohol consumption, smoking, and physical activity in a prospective community-based cohort (n = 360). All patients were passively followed for mortality (2001-2016); 244 were actively followed on average ± SD 5.3 ± 2.1 years (2007-2014). Movement disorder specialists repeatedly assessed motor function (Hoehn & Yahr) and cognition (Mini-Mental State Exam). We used Cox proportional hazards models and inverse probability weights to account for censoring. RESULTS: Coffee, caffeinated tea, moderate alcohol consumption, and physical activity were protective against at least 1 outcome. Smoking and heavy alcohol consumption were associated with increased risks. Coffee was protective against time to Hoehn & Yahr stage 3 (hazard ratio, 0.52; 95% confidence interval, 0.28-1.01), cognitive decline (hazard ratio, 0.23; 95% confidence interval, 0.11, 0.48), and mortality (hazard ratio, 0.47; 95% confidence interval, 0.32-0.69). Relative to moderate drinkers, those who never drank liquor and those who drank more heavily were at an increased risk of Hoehn & Yahr 3 (hazard ratio, 3.48; 95% confidence interval, 1.90-6.38; and hazard ratio, 2.16; 95% confidence interval, 1.03, 4.54, respectively). A history of competitive sports was protective against cognitive decline (hazard ratio, 0.46; 95% confidence interval, 0.22-0.96) and Hoehn & Yahr 3 (hazard ratio, 0.42; 95% confidence interval, 0.23-0.79), as was physical activity measured by metabolic-equivalent hours. Current cigarette smoking was associated with faster cognitive decline (hazard ratio, 3.20; 95% confidence interval, 1.02-10.01). CONCLUSIONS: This population-based study suggests that lifestyle factors influence PD progression and mortality. © 2019 International Parkinson and Movement Disorder Society.

Prenatal Bisphenol A Exposure in Mice Induces Multitissue Multiomics Disruptions Linking to Cardiometabolic Disorders.

The health impacts of endocrine-disrupting chemicals (EDCs) remain debated, and their tissue and molecular targets are poorly understood. In this study, we leveraged systems biology approaches to assess the target tissues, molecular pathways, and gene regulatory networks associated with prenatal exposure to the model EDC bisphenol A (BPA). Prenatal BPA exposure at 5 mg/kg/d, a dose below most reported no-observed-adverse-effect levels, led to tens to thousands of transcriptomic and methylomic alterations in the adipose, hypothalamus, and liver tissues in male offspring in mice, with cross-tissue perturbations in lipid metabolism as well as tissue-specific alterations in histone subunits, glucose metabolism, and extracellular matrix. Network modeling prioritized main molecular targets of BPA, including Pparg, Hnf4a, Esr1, Srebf1, and Fasn as well as numerous less studied targets such as Cyp51 and long noncoding RNAs across tissues, Fa2h in hypothalamus, and Nfya in adipose tissue. Lastly, integrative analyses identified the association of BPA molecular signatures with cardiometabolic phenotypes in mouse and human. Our multitissue, multiomics investigation provides strong evidence that BPA perturbs diverse molecular networks in central and peripheral tissues and offers insights into the molecular targets that link BPA to human cardiometabolic disorders.

Timescales of developmental toxicity impacting on research and needs for intervention.

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision-making must be weighed against the costs and necessary duration of research, as well as the long-term costs to human health because of delayed protection of vulnerable early-life stages of human development and, possibly, future generations. Although two-generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY-BPA-type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.

Early Folic Acid Supplement Initiation and Risk of Adverse Early Childhood Respiratory Health: A Population-based Study.

Objectives Folate plays a vital role in biologic functions yet women often do not meet the recommended dietary intake in pregnancy. It has been suggested that high folic acid intake during pregnancy may increase the risk of respiratory diseases in offspring. However, findings from observational studies in human populations are inconclusive. Methods In this population-based study, we collected self-reported folic acid and prenatal vitamin supplement use during pregnancy 3-6 months postpartum from mothers in Los Angeles whose children were born in 2003. Supplement initiation was based on whichever supplement, either folic acid or prenatal supplements, the women initiated first. In a 2006 follow-up survey, approximately 50% of women were re-contacted to gather information on the child's respiratory health, including symptoms and diagnoses, at approximately 3.5 years of age. Results Overall, timing of folic acid supplement initiation was not associated with wheeze or lower respiratory tract infection, even after accounting for preterm births and censoring at follow-up. However, children born to mothers with a history of atopy (hay fever, eczema or asthma) who initiate folic acid supplements in late pregnancy, compared to first trimester initiators, have 1.67 (95% CI 1.12, 2.49) times the risk of wheeze in the first 3 years of life and 1.88 (95% CI 1.05, 3.34) times the risk of wheeze in the past year. No association was found among children of non-atopic mothers. Conclusions These findings suggest that early folic acid or prenatal supplementation among atopic women may be important to prevent wheeze among offspring.

Pre-conceptual and prenatal supplementary folic acid and multivitamin intake, behavioral problems, and hyperkinetic disorders: A study based on the Danish National Birth Cohort (DNBC).

OBJECTIVE: To evaluate whether early folic acid or multivitamin supplementation during pregnancy prevents diagnosis of hyperkinetic disorders (HKD), treatment for attention deficit hyperactivity disorder (ADHD), and ADHD-like behaviors reported by parents participating in the DNBC for children at age 7. METHODS: HKD diagnosis and ADHD medication use data were obtained from the Danish National Hospital, Central Psychiatric and Pharmaceutical registers. We estimated hazard ratios (HRs) for HKD diagnosis and ADHD medication use and risk ratios (RRs) for parent-reported ADHD behavior collected with the Strength and Difficulties Questionnaire (SDQ), comparing children whose mothers took folic acid or multivitamin supplements early in pregnancy defined as starting periconceptionally (4 weeks prior to their last menstrual period (LMP)) through 8 weeks after their LMP (4-8 weeks), to children whose mothers indicated no supplement use for the same entire period. RESULTS: We identified 384 children (1.1%) with a hospital diagnosis for HKD and 642 children (1.8%) treated with ADHD medication. We found no association between risk of HKD diagnosis or intake of ADHD medication and early maternal folic acid use. However, early multivitamin use was associated with an approximately 30% reduction in risk for HKD diagnosis (aHR: 0.70, 95% CI: 0.52-0.96) and 21% reduction in treatment with ADHD medication (aHR: 0.79, 95% CI: 0.62-0.98). We observed a reduced risk in parent-reported ADHD behaviors, but these results were attenuated after adjustment. CONCLUSION: Our data suggest that multivitamin use in early pregnancy may reduce risk for HKD diagnosis and treatment for ADHD in the offspring.

Coffee consumption is associated with DNA methylation levels of human blood.

Beneficial health effects have been attributed to coffee consumption, but it is not yet known whether epigenetics may have a role in this process. Here we associate epigenome-wide DNA methylation levels to habitual coffee consumption from two studies with blood (2100 and 215 participants), and one with saliva samples (256 participants). Adjusting for age, gender, and blood cell composition, one CpG (cg21566642 near ALPPL2) surpassed genome-wide significance (P=3.7 × 10-10) and from among 10 additional CpGs significant at P≤5.0 × 10-6, six were located within 1500 bps of a transcriptional start site. Results for these 11 top-ranked CpGs remained significant after further adjusting for smoking. Also, methylation levels of another 135 CpGs were influenced by both coffee drinking and smoking (P≤1.0 × 10-7). Functional enrichment analysis suggested that coffee-associated CpGs were located near transcription factor binding (P=1.2 × 10-6) and protein kinase activity genes (P=2.9 × 10-5). Interestingly, when we stratified by menopausal hormone therapy (MHT), methylation differences with coffee consumption were observed only in women who never used MHT. We did not replicate any of the associations found in blood in our saliva samples, suggesting that coffee may affect DNA methylation levels in immune cells of the blood but not in saliva.

The Influence of Pre-natal Supplement Initiation on Preterm Birth Among Majority Hispanic Women in Los Angeles County: The Role of Nativity.

Objectives Despite being encouraged to take pre-natal supplements, suboptimal micronutrient intake is common in pregnancy, especially among Hispanic women. In this study, we assessed whether initiation and timing of pre-natal vitamin use influences the risk of preterm birth. Methods Women who gave birth to singletons in 2003 in Los Angeles County, California, were enrolled into a population-based case-control study. Focusing on non-Hispanic white and Hispanic women, associations between timing of pre-natal supplement use and preterm birth were assessed using logistic regression. Results Among Hispanic mothers, the odds of preterm birth increased the later a woman initiated pre-natal supplement use in pregnancy. The magnitude of this association was larger in US-born compared to foreign-born Hispanic women. Conclusions These findings suggest that nativity may modify the relationship between pre-natal supplement use and preterm birth possibly due to underlying differences in diet composition of Hispanic women by place of birth.

Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders.

OBJECTIVE: To evaluate whether early folic acid supplementation during pregnancy prevents diagnosis of autism spectrum disorders in offspring. METHODS: Information on autism spectrum disorder diagnosis was obtained from the National Hospital Register and the Central Psychiatric Register. We estimated risk ratios for autism spectrum disorders for children whose mothers took folate or multivitamin supplements from 4 weeks prior from the last menstrual period through to 8 weeks after the last menstrual period (-4 to 8 weeks) by three 4-week periods. RESULTS: We did not find an association between early folate or multivitamin intake for autism spectrum disorder (folic acid-adjusted risk ratio: 1.06, 95% confidence interval: 0.82-1.36; multivitamin-adjusted risk ratio: 1.00, 95% confidence interval: 0.82-1.22), autistic disorder (folic acid-adjusted risk ratio: 1.18, 95% confidence interval: 0.76-1.84; multivitamin-adjusted risk ratio: 1.22, 95% confidence interval: 0.87-1.69), Asperger's syndrome (folic acid-adjusted risk ratio: 0.85, 95% confidence interval: 0.46-1.53; multivitamin-adjusted risk ratio: 0.95, 95% confidence interval: 0.62-1.46), or pervasive developmental disorder-not otherwise specified (folic acid-adjusted risk ratio: 1.07, 95% confidence interval: 0.75-1.54; multivitamin: adjusted risk ratio: 0.87, 95% confidence interval: 0.65-1.17) compared with women reporting no supplement use in the same period. CONCLUSION: We did not find any evidence to corroborate previous reports of a reduced risk for autism spectrum disorders in offspring of women using folic acid supplements in early pregnancy.

Gene-Environment Interaction in Parkinson's Disease: Coffee, ADORA2A, and CYP1A2.

BACKGROUND AND PURPOSE: Drinking caffeinated coffee has been reported to provide protection against Parkinson's disease (PD). Caffeine is an adenosine A2A receptor (encoded by the gene ADORA2A) antagonist that increases dopaminergic neurotransmission and Cytochrome P450 1A2 (gene: CYP1A2) metabolizes caffeine; thus, gene polymorphisms in ADORA2A and CYP1A2 may influence the effect coffee consumption has on PD risk. METHODS: In a population-based case-control study (PASIDA) in Denmark (1,556 PD patients and 1,606 birth year- and gender-matched controls), we assessed interactions between lifetime coffee consumption and 3 polymorphisms in ADORA2A and CYP1A2 for all subjects, and incident and prevalent PD cases separately using logistic regression models. We also conducted a meta-analysis combining our results with those from previous studies. RESULTS: We estimated statistically significant interactions for ADORA2A rs5760423 and heavy vs. light coffee consumption in incident (OR interaction = 0.66 [95% CI 0.46-0.94], p = 0.02) but not prevalent PD. We did not observe interactions for CYP1A2 rs762551 and rs2472304 in incident or prevalent PD. In meta-analyses, PD associations with daily coffee consumption were strongest among carriers of variant alleles in both ADORA2A and CYP1A2. CONCLUSION: We corroborated results from a previous report that described interactions between ADORA2A and CYP1A2 polymorphisms and coffee consumption. Our results also suggest that survivor bias may affect results of studies that enroll prevalent PD cases.

Risk of leukemia in relation to exposure to ambient air toxics in pregnancy and early childhood.

There are few established causes of leukemia, the most common type of cancer in children. Studies in adults suggest a role for specific environmental agents, but little is known about any effect from exposures in pregnancy to toxics in ambient air. In our case-control study, we ascertained 69 cases of acute lymphoblastic leukemia (ALL) and 46 cases of acute myeloid leukemia (AML) from California Cancer Registry records of children

Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee.

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df) = 10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7×10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5×10(-8) in GWAIS, and OR = 0.41, P = 3×10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

Outdoor work and risk for Parkinson's disease: a population-based case-control study.

OBJECTIVES: Sunlight is the main contributor to vitamin D in humans. Since inadequate levels of vitamin D have been linked to increased risks for neurodegenerative diseases, we examined whether outdoor work is associated with a reduced risk for Parkinson's disease in a population-based case-control study of Danish men. METHODS: We identified 3819 men with a primary diagnosis of Parkinson's disease in the period 1995-2006 in the Danish National Hospital Register and selected 19,282 age- and sex-matched population controls at random from the Central Population Register. Information on work history was ascertained from the Danish Supplementary Pension Fund and the Central Population Register. Based on trade grouping codes and job titles, we evaluated the extent of outdoor work of study subjects as a proxy of exposure to sunlight. RESULTS: Relying on trade grouping codes, we estimated ORs for study subjects with moderate, frequent and maximal outdoor work compared with exclusive indoor work of 0.90 (95% CI 0.78 to 1.02), 0.86 (95% CI 0.75 to 0.99) and 0.72 (95% CI 0.63 to 0.82), respectively, for Parkinson's disease. Reduced risks were also found for Parkinson's disease among outdoor workers based on study subjects' job titles. CONCLUSIONS: Our findings suggest that men working outdoors have a lower risk for Parkinson's disease. Further studies of measured vitamin D levels in outdoor workers are warranted to clarify a potential inverse association between vitamin D and the risk for Parkinson's disease.