A preliminary assessment of low level arsenic exposure and diabetes mellitus in Cyprus

<p>Abstract</p> <p>Background</p> <p>A preliminary study was undertaken in a community of Cyprus where low-level arsenic (As) concentrations were recently detected in the groundwater that was chronically used to satisfy potable needs of the community. The main objective of the study was to assess the degree of association between orally-ingested As and self-reported type-2 diabetes mellitus (DM) in 317 adult (≥18 years old) volunteers.</p> <p>Methods</p> <p>Cumulative lifetime As exposure (CLAEX) (mg As) was calculated using the median As concentrations in water, individual reported daily water consumption rates, and lifetime exposure duration. Logistic regression models were used to model the probability of self-reported DM and calculate odds ratios (OR) in univariate and multivariate models.</p> <p>Results</p> <p>Significantly higher (p <it><</it> 0.02) CLAEX values were reported for the diabetics (median = 999 mg As) versus non-diabetics (median = 573 mg As), suggesting that As exposure could perhaps be related to the prevalence of DM in the study area, which was 6.6%. The OR for DM, comparing participants in the 80^th versus the 20^th percentiles of low-level As CLAEX index values, was 5.0 (1.03, 24.17), but after adjusting for age, sex, smoking, education, and fish consumption, the As exposure effect on DM was not significant.</p> <p>Conclusions</p> <p>Further research is needed to improve As exposure assessment for the entire Cypriot population while assessing the exact relationship between low-level As exposure and DM.</p

Maternal blood cadmium, lead and arsenic levels, nutrient combinations, and offspring birthweight

Abstract Background Cadmium (Cd), lead (Pb) and arsenic (As) are common environmental contaminants that have been associated with lower birthweight. Although some essential metals may mitigate exposure, data are inconsistent. This study sought to evaluate the relationship between toxic metals, nutrient combinations and birthweight among 275 mother-child pairs. Methods Non-essential metals, Cd, Pb, As, and essential metals, iron (Fe), zinc (Zn), selenium (Se), copper (Cu), calcium (Ca), magnesium (Mg), and manganese (Mn) were measured in maternal whole blood obtained during the first trimester using inductively coupled plasma mass spectrometry. Folate concentrations were measured by microbial assay. Birthweight was obtained from medical records. We used quantile regression to evaluate the association between toxic metals and nutrients due to their underlying wedge-shaped relationship. Ordinary linear regression was used to evaluate associations between birth weight and toxic metals. Results After multivariate adjustment, the negative association between Pb or Cd and a combination of Fe, Se, Ca and folate was robust, persistent and dose-dependent (p < 0.05). However, a combination of Zn, Cu, Mn and Mg was positively associated with Pb and Cd levels. While prenatal blood Cd and Pb were also associated with lower birthweight. Fe, Se, Ca and folate did not modify these associations. Conclusion Small sample size and cross-sectional design notwithstanding, the robust and persistent negative associations between some, but not all, nutrient combinations with these ubiquitous environmental contaminants suggest that only some recommended nutrient combinations may mitigate toxic metal exposure in chronically exposed populations. Larger longitudinal studies are required to confirm these findings

Associations between maternal lifetime stressors and negative events in pregnancy and breast milk-derived extracellular vesicle microRNAs in the programming of intergenerational stress mechanisms (PRISM) pregnancy cohort

Maternal stress is associated with adverse child health. Breast milk microRNAs encapsulated in extracellular vesicles (EVs) are involved in mother-infant biochemical communication during early-life programming. We leverage the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort to investigate associations between maternal stress and breast milk EV-microRNAs. Lifetime stress and negative life events (NLEs) during pregnancy were assessed using the Life Stressor Checklist-Revised (LSCR) and the Crisis in Family Systems-Revised surveys, respectively. RNA was extracted from breast milk EVs (N = 80; collected 6.1 ± 5.9 weeks postnatally), and microRNAs were profiled using the TaqMan OpenArray Human miRNA panel. Associations between stress scores and detection (yes/no) of 173 microRNAs identified in 20–80% of samples were assessed using logistic regression; associations with expression levels of 205 EV-microRNAs identified in >50% of samples were assessed using linear regression. In adjusted models, detection of 60 and 44 EV-microRNAs was associated with higher LSCR and NLE scores, respectively (p 0.2. Enriched KEGG pathways for microRNAs associated with stress scores included fatty acid metabolism and the Hippo signaling pathway. Maternal lifetime stress and NLEs during pregnancy were both associated with detection and expression level of breast milk EV-microRNAs, although associations with microRNA profiles differed between stress measures. Further research is needed to identify biological pathways impacted by associated microRNAs and investigate relationships with child health outcomes. Abbreviations: EV: extracellular vesicle; PRISM: PRogramming of Intergenerational Stress Mechanisms pregnancy cohort; LSCR: Life Stressor Checklist-Revised survey; NLE: negative life event; CRISYS-R: Crisis in Family Systems-Revised survey; KEGG: Kyoto Encyclopaedia of Genes and Genomes; NYC: New York City; SD: standard deviation; IQR: interquartile range; Cq: relative cycle threshold values; PCA: principal component analysi

Breast milk-derived extracellular vesicle miRNAs are associated with maternal asthma and atopy

Background: Breast milk-derived extracellular vesicle (EV) miRNAs may program child health outcomes associated with maternal asthma and atopy. The authors investigated associations between maternal asthma/atopy and EV miRNAs in the Programming of Intergenerational Stress Mechanisms cohort. Methods: Breast milk-derived EV miRNAs collected 6.1 ± 5.9 weeks postnatally (n = 80 mothers) were profiled using the TaqMan OpenArray Human MicroRNA Panel. The authors assessed associations using adjusted robust regression. Results: Nine EV miRNAs were associated with asthma during pregnancy ( a priori criteria: nominal p &lt; 0.05; | Bregression| &gt;0.2). miR-1290 was associated with asthma and atopy during pregnancy (p &lt; 0.05; | Bregression| &gt;0.2). Enriched Kyoto Encyclopedia of Genes and Genomes pathways included TGF-β signaling and extracellular matrix–receptor interaction (false discovery rate &lt;0.05). Conclusion: In this study, maternal asthma and atopy were associated with breast milk-derived EV miRNAs. Additional studies are needed to understand whether EV miRNAs have direct effects on infant and child health. </jats:p

Breast milk-derived extracellular vesicle microRNAs are associated with maternal asthma and atopy. Supplementary data

Spreadsheet S1: 752 known microRNAs measured in breast milk-derived EVs, and number and percent of samples in which microRNAs passed quality control (CQ). For microRNAs that passed QC in at least 50% of samples, normalized ΔCq values were calcualted.     Figure S1: Flowchart of mother-infant pairs with breast milk collected and included in microRNA analyses. Supplemental methods:    Classification of maternal asthma    Classification of maternal atopy    Research Article Reporting Checklist for Bioinformatic and Data Re-analysis Studies. This is a submission requirement for Research Articles reporting the results of a bioinformatic study and/or re-analysis of available online data.   </p

Abstract 14620: LncExACT1 Acts as a Pivotal Switch Between Physiological and Pathological Cardiac Growth

Rationale: Pathological hypertrophy commonly leads to heart failure (HF) and loss of cardiomyocytes, while physiological hypertrophy protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain unclear. While long noncoding RNAs (lncRNAs) are important in cardiac development and disease, their role in physiological hypertrophy is unknown. Objective: To investigate the role of lncRNAs in physiological hypertrophy. Methods and Results: Mice underwent voluntary wheel running for eight weeks or transverse aortic constriction (TAC) for two or ten weeks. RNAseq identified a novel set of lncRNAs altered in exercised hearts, which we termed l ong n on c oding Ex ercise- A ssociated C ardiac T ranscripts (lncExACTs). lncExACT1 was highly conserved and uniquely downregulated in exercised hearts but upregulated in pathological animal models and hearts from HF patients vs controls (1.8-fold; p &lt;0.001, N=24) as well as plasma from HF patients with reduced (2.9-fold; p =0.032, N=16) and preserved ejection fraction (3.4-fold; p =0.006, N=18). In mice, AAV9 lncExACT1 overexpression increased cardiac lncExACT1 7-fold at 16 weeks and increased heart (HW) and lung (LW) weight relative to tibial length (TL), reduced fractional shortening (FS) and increased relative wall thickness (RWT) ( p &lt;0.05 for all). These changes were associated with a pathological gene expression pattern. In contrast, antisense lncExACT1 inhibition reduced cardiac expression 2-fold at 2 weeks and increased HW/TL without an increase in LW/TL, improved cardiac function, and increased RWT ( p &lt;0.05 for all). LncExACT1 inhibition induced a physiological gene expression pattern and increased markers of cardiomyogenesis. LncExACT1 inhibition reduced TAC-induced HW/TL and fibrosis, while increasing FS ( p &lt;0.05 for all). Mechanistic studies revealed that lncExACT1 works by binding miR-222 and as a novel regulator of Hippo/Yap1 signaling through modulation of dachsous cadherin-related 2. Conclusions: lncExACT1 acts as a master switch toggling the heart between physiological and pathological growth and provides a potentially tractable therapeutic target for harnessing the beneficial effects of exercise. </jats:p

lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth

Background: The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis. Methods: RNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid–GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice. Results: We identified exercise-regulated cardiac lncRNAs, called lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure; lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis. Conclusions: These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise. </jats:sec