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      Moderate Prenatal Cadmium Exposure and Adverse Birth Outcomes: a Role for Sex‐Specific Differences?

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          Abstract

          Background/Aim

          Studies on the effects of moderate prenatal exposure to cadmium (Cd) on birth outcomes have been contradictory and it has been suggested that effects may be partly masked by sex‐specific effects. Our aim was to examine the association of Cd exposure in a large group of pregnant women with birth outcomes in the whole group of participants and by sex.

          Methods

          Pregnant women were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood samples for singleton pregnancies with a live birth were analysed for Cd ( n = 4191). Data collected on the infants included anthropometric variables and gestational age at delivery. Data were analysed using SPSS v18.

          Results

          There were adverse associations of maternal blood Cd level with birthweight (unstandardized B coefficient −62.7 g, 95% CI −107.0, −18.4) and crown–heel length (−0.28 cm, 95% CI −0.48, −0.07) in adjusted regression models. On stratification by sex, maternal blood Cd level was adversely associated with birthweight (−87.1 g, 95% CI −144.8, −29.4), head circumference (−0.22 cm, 95% CI −0.39, −0.04), and crown–heel length (−0.44 cm, 95% CI −0.71, −0.18) in girls but not in boys in adjusted regression models.

          Conclusion

          In these pregnant women with moderate prenatal Cd exposure there evidence of adverse associations with birth anthropometry variables in the whole group. However, there was evidence of associations with anthropometric variables in girls that were not evident in boys. Sex‐specific effects require further investigation in large cohorts as a possible contributor to the lack of associations generally found in mixed‐sex studies.

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          Most cited references29

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          On the pitfalls of adjusting for gestational age at birth.

          Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified.
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            Cadmium exposure and the epigenome: Exposure-associated patterns of DNA methylation in leukocytes from mother-baby pairs.

            Cadmium (Cd) is prevalent in the environment yet understudied as a developmental toxicant. Cd partially crosses the placental barrier from mother to fetus and is linked to detrimental effects in newborns. Here we examine the relationship between levels of Cd during pregnancy and 5-methylcytosine (5mC) levels in leukocyte DNA collected from 17 mother-newborn pairs. The methylation of cytosines is an epigenetic mechanism known to impact transcriptional signaling and influence health endpoints. A methylated cytosine-guanine (CpG) island recovery assay was used to assess over 4.6 million sites spanning 16,421 CpG islands. Exposure to Cd was classified for each mother-newborn pair according to maternal blood levels and compared with levels of cotinine. Subsets of genes were identified that showed altered DNA methylation levels in their promoter regions in fetal DNA associated with levels of Cd (n = 61), cotinine (n = 366), or both (n = 30). Likewise, in maternal DNA, differentially methylated genes were identified that were associated with Cd (n = 92) or cotinine (n = 134) levels. While the gene sets were largely distinct between maternal and fetal DNA, functional similarities at the biological pathway level were identified including an enrichment of genes that encode for proteins that control transcriptional regulation and apoptosis. Furthermore, conserved DNA motifs with sequence similarity to specific transcription factor binding sites were identified within the CpG islands of the gene sets. This study provides evidence for distinct patterns of DNA methylation or "footprints" in fetal and maternal DNA associated with exposure to Cd.
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              Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight

              Dietary cadmium exposure was recently found to alter DNA methylation in adults, but data on effects early in life are lacking. Our objective was to evaluate associations between prenatal cadmium exposure, DNA methylation and birth weight. In total 127 mother-child pairs from rural Bangladesh were studied. For comparison, we included 56 children at 4.5 y. Cadmium concentrations in mothers’ blood (gestational week 14) and children’s urine were measured by ICPMS. Global DNA methylation was analyzed by Infinium HumanMethylation450K BeadChip in cord blood and children’s blood. Maternal cadmium exposure was associated with cord blood DNA methylation (p-value 0.50), whereas most associations in girls were inverse; only 29% were positive (rS > 0.45). In girls we found overrepresentation of methylation changes in genes associated with organ development, morphology and mineralization of bone, whereas changes in boys were found in cell death-related genes. Several individual CpG sites that were positively associated with cadmium were inversely correlated with birth weight, although none statistically significant after correction for multiple comparisons. The associations were, however, fairly robust in multivariable-adjusted linear regression models. We identified CpG sites that were significantly associated with cadmium exposure in both newborns and 4.5-y-old children. In conclusion, cadmium exposure in early life appears to alter DNA methylation differently in girls and boys. This is consistent with previous findings of sex-specific cadmium toxicity. Cadmium-related changes in methylation were also related to lower birth weight.
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                Author and article information

                Contributors
                Caroline.m.taylor@bristol.ac.uk
                Journal
                Paediatr Perinat Epidemiol
                Paediatr Perinat Epidemiol
                10.1111/(ISSN)1365-3016
                PPE
                Paediatric and Perinatal Epidemiology
                John Wiley and Sons Inc. (Hoboken )
                0269-5022
                1365-3016
                25 October 2016
                November 2016
                : 30
                : 6 ( doiID: 10.1111/ppe.2016.30.issue-6 )
                : 603-611
                Affiliations
                [ 1 ] Centre for Child and Adolescent Health School of Social and Community MedicineUniversity of Bristol BristolUK
                Author notes
                [*] [* ] Correspondence:

                Caroline M. Taylor, Centre for Child and Adolescent Health, School of Social and Community Medicine, Oakfield House, Oakfield Grove, University of Bristol, Bristol BS8 2BN, UK.

                E‐mail: Caroline.m.taylor@ 123456bristol.ac.uk

                Article
                PPE12318
                10.1111/ppe.12318
                5111596
                27778365
                22e23a96-d3c2-4325-95d9-361d347fa941
                © 2016 The Authors. Paediatric and Perinatal Epidemiology Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 0, Tables: 5, Pages: 9, Words: 6388
                Funding
                Funded by: UK Medical Research Council
                Funded by: Wellcome Trust
                Award ID: 102215/2/13/2
                Funded by: University of Bristol
                Funded by: Wellcome Trust Career Re‐entry Fellowship
                Award ID: 104077/Z/14/Z
                Categories
                Original Article
                Childhood Outcomes
                Custom metadata
                2.0
                ppe12318
                November 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.7 mode:remove_FC converted:16.11.2016

                Pediatrics
                alspac,cadmium,pregnancy,environment,smoking,child,birth outcomes,heavy metals
                Pediatrics
                alspac, cadmium, pregnancy, environment, smoking, child, birth outcomes, heavy metals

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