Associations between Maternal Cadmium Exposure with Risk of Preterm Birth and Low Birth Weight: Effect of Mediterranean Diet Adherence on Affected Prenatal Outcomes

Prenatal cadmium exposure at non-occupational levels has been associated with poor birth outcomes. The intake of essential metals, such as iron and selenium, may mitigate cadmium exposure effects. However, at high levels, these metals can be toxic. The role of dietary patterns rich in these metals is less studied. We used a linear and logistic regression in a cohort of 185 mother–infant pairs to assess if a Mediterranean diet pattern during pregnancy modified the associations between prenatal cadmium exposure and (1) birth weight and (2) preterm birth. We found that increased cadmium exposure during pregnancy was associated with lower birth weight (β = −210.4; 95% CI: −332.0, −88.8; p = 0.008) and preterm birth (OR = 0.11; 95% CI: 0.01, 0.72; p = 0.04); however, these associations were comparable in offspring born to women reporting high adherence to a Mediterranean diet (β = −274.95; 95% CI: −701.17, 151.26; p = 0.20) and those with low adherence (β = −64.76; 95% CI: −359.90, 230.37; p = 0.66). While the small sample size limits inference, our findings suggest that adherence to a Mediterranean dietary pattern may not mitigate cadmium exposure effects. Given the multiple organs targeted by cadmium and its slow excretion rate, larger studies are required to clarify these findings

Periconceptional Maternal Mediterranean Diet Is Associated With Favorable Offspring Behaviors and Altered CpG Methylation of Imprinted Genes

Background: Maternal diet during pregnancy has been shown to influence the child neuro-developmental outcomes. Studies examining effects of dietary patterns on offspring behavior are sparse.Objective: Determine if maternal adherence to a Mediterranean diet is associated with child behavioral outcomes assessed early in life, and to evaluate the role of differentially methylated regions (DMRs) regulating genomically imprinted genes in these associations.Methods: Among 325 mother/infant pairs, we used regression models to evaluate the association between tertiles of maternal periconceptional Mediterranean diet adherence (MDA) scores derived from a Food Frequency Questionnaire, and social and emotional scores derived from the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire in the second year of life. Methylation of nine genomically imprinted genes was measured to determine if MDA was associated with CpG methylation.Results: Child depression was inversely associated with maternal MDA (Bonferroni-corrected p = 0.041). While controlling for false-discovery, compared to offspring of women with the lowest MDA tertile, those with MDA scores in middle and high MDA tertiles had decreased odds for atypical behaviors [OR (95% CI) = 0.40 (0.20, 0.78) for middle and 0.40 (0.17, 0.92) for highest tertile], for maladaptive behaviors [0.37 (0.18, 0.72) for middle tertile and 0.42 (0.18, 0.95) for highest tertile] and for an index of autism spectrum disorder behaviors [0.46 (0.23, 0.90) for middle and 0.35 (0.15, 0.80) for highest tertile]. Offspring of women with the highest MDA tertile were less likely to exhibit depressive [OR = 0.28 (0.12, 0.64)] and anxiety [0.42 (0.18, 0.97)] behaviors and increased odds of social relatedness [2.31 (1.04, 5.19)] behaviors when compared to low MDA mothers. Some associations varied by sex. Perinatal MDA score was associated with methylation differences for imprinted control regions of PEG10/SGCE [females: Beta (95% CI) = 1.66 (0.52, 2.80) – Bonferroni-corrected p = 0.048; males: -0.56 (-1.13, -0.00)], as well as both MEG3 and IGF2 in males [0.97 (0.00, 1.94)] and -0.92 (-1.65, -0.19) respectively.Conclusion: In this ethnically diverse cohort, maternal adherence to a Mediterranean diet in early pregnancy was associated with favorable neurobehavioral outcomes in early childhood and with sex-dependent methylation differences of MEG3, IGF2, and SGCE/PEG10 DMRs

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

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers

Geographic clustering of elevated blood heavy metal levels in pregnant women

Abstract Background Cadmium (Cd), lead (Pb), mercury (Hg), and arsenic (As) exposure is ubiquitous and has been associated with higher risk of growth restriction and cardiometabolic and neurodevelopmental disorders. However, cost-efficient strategies to identify at-risk populations and potential sources of exposure to inform mitigation efforts are limited. The objective of this study was to describe the spatial distribution and identify factors associated with Cd, Pb, Hg, and As concentrations in peripheral blood of pregnant women. Methods Heavy metals were measured in whole peripheral blood of 310 pregnant women obtained at gestational age ~12 weeks. Prenatal residential addresses were geocoded and geospatial analysis (Getis-Ord Gi* statistics) was used to determine if elevated blood concentrations were geographically clustered. Logistic regression models were used to identify factors associated with elevated blood metal levels and cluster membership. Results Geospatial clusters for Cd and Pb were identified with high confidence (p-value for Gi* statistic <0.01). The Cd and Pb clusters comprised 10.5 and 9.2 % of Durham County residents, respectively. Medians and interquartile ranges of blood concentrations (μg/dL) for all participants were Cd 0.02 (0.01–0.04), Hg 0.03 (0.01–0.07), Pb 0.34 (0.16–0.83), and As 0.04 (0.04–0.05). In the Cd cluster, medians and interquartile ranges of blood concentrations (μg/dL) were Cd 0.06 (0.02–0.16), Hg 0.02 (0.00–0.05), Pb 0.54 (0.23–1.23), and As 0.05 (0.04–0.05). In the Pb cluster, medians and interquartile ranges of blood concentrations (μg/dL) were Cd 0.03 (0.02–0.15), Hg 0.01 (0.01–0.05), Pb 0.39 (0.24–0.74), and As 0.04 (0.04–0.05). Co-exposure with Pb and Cd was also clustered, the p-values for the Gi* statistic for Pb and Cd was <0.01. Cluster membership was associated with lower education levels and higher pre-pregnancy BMI. Conclusions Our data support that elevated blood concentrations of Cd and Pb are spatially clustered in this urban environment compared to the surrounding areas. Spatial analysis of metals concentrations in peripheral blood or urine obtained routinely during prenatal care can be useful in surveillance of heavy metal exposure

Association between DNA methylation and ADHD symptoms from birth to school age : a prospective meta-analysis

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p <0.05) in either of the EWAS were correlated between timepoints (rho = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p <1 x 10(-7)), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p <1 x 10(-7). In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.Peer reviewe

Mapping Copy Number Variation by Population Scale Genome Sequencing

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.Organismic and Evolutionary Biolog

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Daily survey participation and positive changes in mental health symptom scores among Royal Canadian Mounted Police Cadets

IntroductionRoyal Canadian Mounted Police (RCMP) officers self-report high levels of mental health disorder symptoms, such as alcohol use disorder, generalized anxiety disorder, major depressive disorder, panic disorder, and posttraumatic stress disorder. Participation in regular mental health monitoring has been associated with improved mental health disorder symptom reporting and may provide an accessible tool to support RCMP mental health. The current study assessed relationships between self-reported mental health disorder symptoms and the completion of daily surveys (i.e., daily mental health disorder symptom monitoring) by RCMP cadets during the Cadet Training Program (CTP).MethodsParticipants were RCMP cadets (n = 394; 76.1% men) in the Standard Training Program who completed the 26-week CTP and daily self-monitoring surveys, as well as full mental health assessments at pre-training (i.e., starting the CTP) and pre-deployment (i.e., ~2 weeks prior to deployment to the field). Symptoms of alcohol use disorder, generalized anxiety disorder, major depressive disorder, panic disorder, and posttraumatic stress disorder were assessed. Changes in mental health disorder symptom reporting from pre-training to pre-deployment were calculated. Spearman’s rank correlations were estimated for number of daily surveys completed and change in mental health disorder symptom scores between pre-training and pre-deployment.ResultsThere were statistically significant inverse relationships between number of daily surveys completed and number of mental health disorder symptoms reported; specifically, cadets who completed more daily surveys during CTP reported fewer symptoms of alcohol use disorder, generalized anxiety disorder, major depressive disorder, panic disorder, and posttraumatic stress disorder.ConclusionAn inverse correlation between number of daily surveys completed and mental health disorder symptom scores indicated that participation in daily mental health monitoring was associated with improvements in self-reported mental health disorder symptoms between pre-training and pre-deployment. Regular self-monitoring of mental health disorder symptoms may help to mitigate mental health challenges among RCMP cadets and officers