Publications by authors named "Corina Lesseur"

38 Publications

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.

Nat Commun 2021 08 24;12(1):5095. Epub 2021 Aug 24.

Universitat Pompeu Fabra, Barcelona, Spain.

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24558-yDOI Listing
August 2021

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

Urinary glyphosate concentration in pregnant women in relation to length of gestation.

Environ Res 2021 Jul 30;203:111811. Epub 2021 Jul 30.

Department of Environmental Medicine and Public Heath, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Human exposure to glyphosate-based herbicides (GBH) is increasing rapidly worldwide. Most existing studies on health effects of glyphosate have focused on occupational settings and cancer outcomes and few have examined this common exposure in relation to the health of pregnant women and newborns in the general population. We investigated associations between prenatal glyphosate exposure and length of gestation in The Infant Development and the Environment Study (TIDES), a multi-center US pregnancy cohort. Glyphosate and its primary degradation product [aminomethylphosphonic acid (AMPA)] were measured in urine samples collected during the second trimester from 163 pregnant women: 69 preterm births (<37 weeks) and 94 term births, the latter randomly selected as a subset of TIDES term births. We examined the relationship between exposure and length of gestation using multivariable logistic regression models (dichotomous outcome; term versus preterm) and with weighted time-to-event Cox proportional hazards models (gestational age in days). We conducted these analyses in the overall sample and secondarily, restricted to women with spontaneous deliveries (n = 90). Glyphosate and AMPA were detected in most urine samples (>94 %). A shortened gestational length was associated with maternal glyphosate (hazard ratio (HR): 1.31, 95 % confidence interval (CI) 1.00-1.71) and AMPA (HR: 1.32, 95%CI: 1.00-1.73) only among spontaneous deliveries using adjusted Cox proportional hazards models. In binary analysis, glyphosate and AMPA were not associated with preterm birth risk (<37 weeks). Our results indicate widespread exposure to glyphosate in the general population which may impact reproductive health by shortening length of gestation. Given the increasing exposure to GBHs and the public health burden of preterm delivery, larger confirmatory studies are needed, especially in vulnerable populations such as pregnant women and newborns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111811DOI Listing
July 2021

Maternal urinary levels of glyphosate during pregnancy and anogenital distance in newborns in a US multicenter pregnancy cohort.

Environ Pollut 2021 Jul 22;280:117002. Epub 2021 Mar 22.

Department of Environmental Medicine and Public Heath, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Human exposure to glyphosate has become ubiquitous because of its increasing agricultural use. Recent studies suggest endocrine disrupting effects of glyphosate. Specifically, in our work in rodents, low-dose early-life exposure to Roundup® (glyphosate-based herbicide) lengthened anogenital distance (AGD) in male and female offspring. AGD is a marker of the prenatal hormone milieu in rodents and humans. The relationship between glyphosate exposure and AGD has not been studied in humans. We conducted a pilot study in 94 mother-infant pairs (45 female and 49 male) from The Infant Development and the Environment Study (TIDES). For each infant, two AGD measurements were collected after birth; the anopenile (AGD-AP) and anoscrotal (AGD-AS) distances for males, and anoclitoral (AGD-AC) and anofourchette distances (AGD-AF) for females. We measured levels of glyphosate and its degradation product aminomethylphosphonic acid (AMPA) in 2nd trimester maternal urine samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. We assessed the relationship between exposure and AGD using sex-stratified multivariable linear regression models. Glyphosate and AMPA were detected in 95% and 93% of the samples (median 0.22 ng/mL and 0.14 ng/mL, respectively). Their concentrations were moderately correlated (r = 0.55, p = 5.7 × 10). In female infants, high maternal urinary glyphosate (above the median) was associated with longer AGD-AC (β = 1.48, 95%CI (-0.01, 3.0), p = 0.05), but this was not significant after covariate adjustment. Increased AMPA was associated with longer AGD-AF (β = 1.96, 95%CI (0.44, 3.5), p = 0.01) after adjusting for infant size and age at AGD exam. No associations were detected in male offspring. These preliminary findings partially reproduce our previous results in rodents and suggest that glyphosate is a sex-specific endocrine disruptor with androgenic effects in humans. Given the increasing glyphosate exposures in the US population, larger studies should evaluate potential developmental effects on endocrine and reproductive systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2021.117002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165010PMC
July 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Low-dose exposure of glyphosate-based herbicides disrupt the urine metabolome and its interaction with gut microbiota.

Sci Rep 2021 Feb 5;11(1):3265. Epub 2021 Feb 5.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, USA.

Glyphosate-based herbicides (GBHs) can disrupt the host microbiota and influence human health. In this study, we explored the potential effects of GBHs on urinary metabolites and their interactions with gut microbiome using a rodent model. Glyphosate and Roundup (equal molar for glyphosate) were administered at the USA glyphosate ADI guideline (1.75 mg/kg bw/day) to the dams and their pups. The urine metabolites were profiled using non-targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS). Our results found that overall urine metabolite profiles significantly differed between dams and pups and between female and male pups. Specifically, we identified a significant increase of homocysteine, a known risk factor of cardiovascular disease in both Roundup and glyphosate exposed pups, but in males only. Correlation network analysis between gut microbiome and urine metabolome pointed to Prevotella to be negatively correlated with the level of homocysteine. Our study provides initial evidence that exposures to commonly used GBH, at a currently acceptable human exposure dose, is capable of modifying urine metabolites in both rat adults and pups. The link between Prevotella-homocysteine suggests the potential role of GBHs in modifying the susceptibility of homocysteine, which is a metabolite that has been dysregulated in related diseases like cardiovascular disease or inflammation, through commensal microbiome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-82552-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864973PMC
February 2021

Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms.

Genet Epidemiol 2020 11 24;44(8):924-933. Epub 2020 Jul 24.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240308PMC
November 2020

Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: An epigenome-wide study of two U.S. birth cohorts.

Environ Int 2020 04 31;137:105508. Epub 2020 Jan 31.

Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; Children's Environmental Health and Disease Prevention Research Center at Dartmouth, Dartmouth College, Lebanon, NH, USA. Electronic address:

Background/aim: Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior.

Methods: We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores.

Results: We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (β-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]).

Conclusions: Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2020.105508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722519PMC
April 2020

Associations of maternal diet and placenta leptin methylation.

Mol Cell Endocrinol 2020 04 29;505:110739. Epub 2020 Jan 29.

Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, USA.

Background: Maternal diet is an important factor in prenatal development that also has implications for disease risk later in life. The adipokine leptin is a key regulator of energy homeostasis and may be involved in the association between maternal nutrition, maternal obesity, and infant outcomes. DNA methylation of placenta genes may occur in response to exposures and may program subsequent infant development. This study examined maternal diet, placenta leptin gene DNA methylation, and neonatal growth in a sample of healthy neonates and their mothers.

Methods: Mothers and their healthy neonates (N = 135) were recruited within 1-2 days following delivery at Women and Infants Hospital in Providence, RI. A structured interview was conducted to assess maternal dietary intake. Maternal pre-pregnancy weight, weight gain during pregnancy, maternal health, medications, and vitamin use were obtained from medical records. Bisulfite pyrosequencing was used to measure methylation of CpG sites in the promoter region of the placenta leptin gene and determine genotype of the leptin single nucleotide polymorphism (SNP) rs2167270, which is known to influence leptin methylation. Bivariate analyses and linear regression models were used to evaluate associations of demographics, diet, and mean leptin methylation.

Results: Genotype was a significant predictor of placenta leptin DNA methylation (p < .01), and after controlling for this and other relevant maternal and infant covariates, lower levels of leptin methylation were significantly associated with greater intake of carbohydrates (p < .05), in particular added sugars (p < .05) and white/refined carbohydrates (p < .05). Total caloric intake was also associated with placenta leptin methylation (p < .05), however after controlling for relevant covariates, significance diminished to trend-level. There were no significant associations of placenta leptin methylation and intake of protein (p > .05) or fat (p > .05).

Conclusion: These findings underline the importance of intake of carbohydrate consumption for methylation of the placenta leptin gene. Because methylation reduces gene transcription, lower methylation may indicate a placenta response to high caloric intake and carbohydrate food that would result in higher levels of this hormone during fetal development. Further investigation of the developmental ramifications of epigenetic changes to placenta leptin methylation should be pursued.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2020.110739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185035PMC
April 2020

Fluoride exposure and kidney and liver function among adolescents in the United States: NHANES, 2013-2016.

Environ Int 2019 11 8;132:105012. Epub 2019 Aug 8.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Hepato- and nephrotoxicity of fluoride have been demonstrated in animals, but few studies have examined potential effects in humans. This population-based study examines the relationship between chronic low-level fluoride exposure and kidney and liver function among United States (U.S.) adolescents. This study aimed to evaluate whether greater fluoride exposure is associated with altered kidney and liver parameters among U.S. youth.

Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2013-2016). We analyzed data from 1983 and 1742 adolescents who had plasma and water fluoride measures respectively and did not have kidney disease. Fluoride was measured in plasma and household tap water. Kidney parameters included estimated glomerular filtration rate (calculated by the original Schwartz formula), serum uric acid, and the urinary albumin to creatinine ratio. Liver parameters were assessed in serum and included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, gamma-glutamyl transferase, and albumin. Survey-weighted linear regression examined relationships between fluoride exposure and kidney and liver parameters after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons.

Results: The average age of adolescents was 15.4 years. Median water and plasma fluoride concentrations were 0.48 mg/L and 0.33 μmol/L respectively. A 1 μmol/L increase in plasma fluoride was associated with a 10.36 mL/min/1.73 m lower estimated glomerular filtration rate (95% CI: -17.50, -3.22; p = 0.05), a 0.29 mg/dL higher serum uric acid concentration (95% CI: 0.09, 0.50; p = 0.05), and a 1.29 mg/dL lower blood urea nitrogen concentration (95%CI: -1.87, -0.70; p < 0.001). A 1 mg/L increase in water fluoride was associated with a 0.93 mg/dL lower blood urea nitrogen concentration (95% CI: -1.44, -0.42; p = 0.007).

Conclusions: Fluoride exposure may contribute to complex changes in kidney and liver related parameters among U.S. adolescents. As the study is cross-sectional, reverse causality cannot be ruled out; therefore, altered kidney and/or liver function may impact bodily fluoride absorption and metabolic processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2019.105012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754771PMC
November 2019

The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system.

Environ Health 2019 03 12;18(1):15. Epub 2019 Mar 12.

Cesare Maltoni Cancer Research Center (CMCRC), Ramazzini Institute (RI), Via Saliceto, 3, 40010, Bentivoglio, Bologna, Italy.

Background: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats.

Methods: Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups.

Results: In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure.

Conclusions: The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12940-019-0453-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413565PMC
March 2019

Shared heritability and functional enrichment across six solid cancers.

Nat Commun 2019 01 25;10(1):431. Epub 2019 Jan 25.

Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r = 0.57, p = 4.6 × 10), breast and ovarian cancer (r = 0.24, p = 7 × 10), breast and lung cancer (r = 0.18, p =1.5 × 10) and breast and colorectal cancer (r = 0.15, p = 1.1 × 10). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-08054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347624PMC
January 2019

Adverse Maternal Metabolic Intrauterine Environment and Placental Epigenetics: Implications for Fetal Metabolic Programming.

Curr Environ Health Rep 2018 12;5(4):531-543

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New York, NY, 10029, USA.

Purpose Of Review: Herein, we summarize existent epidemiological studies relating adverse maternal metabolic environments of maternal obesity and gestational diabetes and placental DNA methylation.

Recent Findings: Multiple studies have evaluated associations between intrauterine exposure to gestational diabetes and/or maternal glucose levels and DNA methylation at candidate metabolic genes as well as in epigenome-wide studies. Some of the genomic regions more consistently associated include lipid-related genes (LPL and PPARGC1A), the major histocompatibility complex (MHC), and imprinted genes. Studies solely focused on maternal obesity influences on the placental epigenome are scarce. Understanding the placental mechanisms involved in fetal metabolic programming could lead to discovery of placental biomarkers at birth that predict later-life metabolic risk. Moving forward is important to standardize methods utilized in epigenetics research; consistent methodology can help interpret disparate findings. Larger studies with longitudinal follow-up are needed to address future challenges in fetal programming research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40572-018-0217-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599179PMC
December 2018

Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.

Nat Commun 2018 09 25;9(1):3927. Epub 2018 Sep 25.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892-9768, MD, USA.

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05890-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156406PMC
September 2018

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Int J Epidemiol 2019 06;48(3):751-766

Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany.

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.

Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.

Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.

Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyy140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659464PMC
June 2019

The Ramazzini Institute 13-week pilot study on glyphosate and Roundup administered at human-equivalent dose to Sprague Dawley rats: effects on the microbiome.

Environ Health 2018 05 29;17(1):50. Epub 2018 May 29.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1428 Madison, New York, NY, 10029, USA.

Background: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including its effects on microbiome. The present pilot study examines whether exposure to GBHs at doses of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero, may modify the composition of gut microbiome in Sprague Dawley (SD) rats.

Methods: Glyphosate alone and Roundup, a commercial brand of GBHs, were administered in drinking water at doses comparable to the US glyphosate ADI (1.75 mg/kg bw/day) to F0 dams starting from the gestational day (GD) 6 up to postnatal day (PND) 125. Animal feces were collected at multiple time points from both F0 dams and F1 pups. The gut microbiota of 433 fecal samples were profiled at V3-V4 region of 16S ribosomal RNA gene and further taxonomically assigned and assessed for diversity analysis. We tested the effect of exposure on overall microbiome diversity using PERMANOVA and on individual taxa by LEfSe analysis.

Results: Microbiome profiling revealed that low-dose exposure to Roundup and glyphosate resulted in significant and distinctive changes in overall bacterial composition in F1 pups only. Specifically, at PND31, corresponding to pre-pubertal age in humans, relative abundance for Bacteriodetes (Prevotella) was increased while the Firmicutes (Lactobacillus) was reduced in both Roundup and glyphosate exposed F1 pups compared to controls.

Conclusions: This study provides initial evidence that exposures to commonly used GBHs, at doses considered safe, are capable of modifying the gut microbiota in early development, particularly before the onset of puberty. These findings warrant future studies on potential health effects of GBHs in early development such as childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12940-018-0394-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972442PMC
May 2018

Pulmonary microRNA profiling: implications in upper lobe predominant lung disease.

Clin Epigenetics 2017 30;9:56. Epub 2017 May 30.

Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH USA.

Background: Numerous pulmonary diseases manifest with upper lobe predominance including cystic fibrosis, smoking-related chronic obstructive pulmonary disease, and tuberculosis. Zonal hypoxia, characteristic of these pulmonary maladies, and oxygen stress in general is known to exert profound effects on various important aspects of cell biology. Lung macrophages are major participants in the pulmonary innate immune response and regional differences in macrophage responsiveness to hypoxia may contribute in the development of lung disease. MicroRNAs are ubiquitous regulators of human biology and emerging evidence indicates altered microRNA expression modulates respiratory disease processes. The objective of this study is to gain insight into the epigenetic and cellular mechanisms influencing regional differences in lung disease by investigating effect of hypoxia on regional microRNA expression in the lung. All studies were performed using primary alveolar macrophages ( = 10) or bronchoalveolar lavage fluid ( = 16) isolated from human subjects. MicroRNA was assayed via the NanoString nCounter microRNA assay.

Results: Divergent molecular patterns of microRNA expression were observed in alternate lung lobes, specifically noted was disparate expression of miR-93 and miR-4454 in alveolar macrophages along with altered expression of miR-451a and miR-663a in bronchoalveolar lavage fluid. Gene ontology was used to identify potential downstream targets of divergent microRNAs. Targets include cytokines and matrix metalloproteinases, molecules that could have a significant impact on pulmonary inflammation and fibrosis.

Conclusions: Our findings show variant regional microRNA expression associated with hypoxia in alveolar macrophages and BAL fluid in the lung-upper vs lower lobe. Future studies should address whether these specific microRNAs may act intracellularly, in a paracrine/endocrine manner to direct the innate immune response or may ultimately be involved in pulmonary host-to-pathogen trans-kingdom cross-talk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-017-0355-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450072PMC
March 2018

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.

Nat Genet 2016 12 17;48(12):1544-1550. Epub 2016 Oct 17.

Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10) than in HPV-negative (OR = 0.75, P = 0.16) cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131845PMC
December 2016

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior.

Epigenetics 2016 08 1;11(8):603-13. Epub 2016 Jul 1.

a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA.

The placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 × 10(-7)) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are over-represented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15592294.2016.1195534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990225PMC
August 2016

Prenatal Programming of Infant Neurobehaviour in a Healthy Population.

Paediatr Perinat Epidemiol 2016 07 23;30(4):367-75. Epub 2016 Mar 23.

Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH.

Background: Identifying the prenatal origins of mental conditions is of increasing interest, yet most studies have focused on high-risk populations and cannot disentangle prenatal and postnatal programming effects. Thus, we examined whether profiles of neurobehaviour indicative of future risk could be identified in healthy 1-3-day-old infants, and examined associations with perinatal risk factors.

Methods: Participants included 627 healthy mothers and term infants from a population-based US cohort. Neurobehaviour was assessed within 24-72 h after delivery with the NICU Network Neurobehavioural Scales (NNNS). A model-based clustering algorithm was used to derive neurobehavioural profiles from NNNS scores. Maternal health histories, pregnancy conditions and behaviours, labour/delivery factors, and infant attributes were examined in relation to the neurobehavioural profiles.

Results: Seven discrete neurobehavioural profiles were identified, including one average functioning profile, and two inversely patterned below and above average profiles. Higher pregnancy weight gain (OR 1.44, 95% CI 1.10, 1.88) and birthweight percentiles (OR 1.46, 95% CI 1.10, 1.95) were associated with greater odds of below average newborn neurobehaviour. Above average neurobehaviour was associated with experiencing longer gestations (OR 1.29, 95% CI 1.02, 1.64) and higher 5-min APGAR scores (OR 2.43, 95% CI 1.07, 5.52). Maternal pregnancy alcohol use (OR 0.54, 95% CI 0.33, 0.89), and fetal distress (OR 0.10, 95% CI 0.01, 0.72) were associated with lower likelihood of having average neurobehaviour.

Conclusion: Distinct profiles of neurobehaviour can be derived in a healthy population of newborns, with different sets of perinatal factors predicting different patterns of neurobehaviour. These findings suggest a potential in utero origin for mental health risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054721PMC
http://dx.doi.org/10.1111/ppe.12294DOI Listing
July 2016

Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment.

Epigenomics 2015 Aug 7;7(5):767-79. Epub 2015 Sep 7.

Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.

Aim: To determine associations between methylation of NR3C1, HSD11B2, FKBP5 and ADCYAP1R1 and newborn neurobehavioral outcomes.

Methods: In 537 newborns, placental methylation was quantified using bisulfite pyrosequencing. Profiles of neurobehavior were derived via the Neonatal Intensive Care Unit Network Neurobehavioral Scales. Using exploratory factor analysis, the relationships between methylation factor scores and neurobehavioral profiles were examined.

Results: Increased scores of the factor characterized by NR3C1 methylation were associated with membership in a reactive, poorly regulated profile (odds ratio: 1.47; 95% CI: 1.00-2.18), while increased scores of the factor characterized by HSD11B2 methylation reduced this risk.

Conclusion: These results suggest that coordinated regulation of these genes influences neurobehavior and demonstrates the importance of examining these alterations in a harmonized fashion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi.15.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772971PMC
August 2015

Epigenome-wide and transcriptome-wide analyses reveal gestational diabetes is associated with alterations in the human leukocyte antigen complex.

Clin Epigenetics 2015 5;7:79. Epub 2015 Aug 5.

Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115 USA ; Harvard University Center for the Environment, Harvard University, Cambridge, MA 02138 USA ; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA 02115 USA.

Background: Gestational diabetes mellitus (GDM) affects approximately 10 % of pregnancies in the United States and increases the risk of adverse health outcomes in the offspring. These adult disease propensities may be set by anatomical and molecular alterations in the placenta associated with GDM.

Results: To assess the mechanistic aspects of fetal programming, we measured genome-wide methylation (Infinium HumanMethylation450 BeadChips) and expression (Affymetrix transcriptome microarrays) in placental tissue of 41 GDM cases and 41 matched pregnancies without maternal complications from the Harvard Epigenetic Birth Cohort. Specific transcriptional and epigenetic perturbations associated with GDM status included alterations in the major histocompatibility complex (MHC) region, which were validated in an independent cohort, the Rhode Island Child Health Study. Gene ontology enrichment among gene regulation influenced by GDM revealed an over-representation of immune response pathways among differential expression, reflecting these coordinated changes in the MHC region. This differential methylation and expression may be capturing shifts in cellular composition, reflecting physiological changes in the placenta associated with GDM.

Conclusions: Our study represents the largest investigation of transcriptomic and methylomic differences associated with GDM, providing comprehensive insight into how GDM shapes the intrauterine environment, which may have implications for fetal (re)programming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-015-0116-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524439PMC
August 2015

Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children.

Dev Psychopathol 2015 May;27(2):577-85

Brown University Alpert Medical School.

Epigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR), which is a key regulator of the hypothalamic-pituitary-adrenal axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n = 74 with child welfare documentation of moderate-severe maltreatment in the past 6 months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1(D), 1(F), and 1(H) of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1(D) and 1(F) in the promoter of the GR gene. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0954579415000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014375PMC
May 2015

The Role of Placental 11-Beta Hydroxysteroid Dehydrogenase Type 1 and Type 2 Methylation on Gene Expression and Infant Birth Weight.

Biol Reprod 2015 Jun 18;92(6):149. Epub 2015 Mar 18.

Departments of Pharmacology and Toxicology and of Epidemiology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire

Maternal stress has been linked to infant birth weight outcomes, which itself may be associated with health later in life. The placenta acts as a master regulator for the fetal environment, mediating intrauterine exposures to stress through the activity of genes regulating glucocorticoids, including the 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1 and 2 genes, and so we hypothesized that variation in these genes will be associated with infant birth weight. We investigated DNA methylation levels at six sites across the two genes, as well as mRNA expression for each, and the relationship to infant birth weight. Logistic regressions correcting for potential confounding factors revealed a significant association between methylation at a single CpG site within HSD11B1 and being born large for gestational age. In addition, our analysis identified correlations between methylation and gene expression, including sex-specific transcriptional regulation of HSD11B2. Our work is one of the first comprehensive views of DNA methylation and expression in the placenta for both HSD11B types 1 and 2, linking epigenetic alterations with the regulation of fetal stress and birth weight outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1095/biolreprod.115.128066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652612PMC
June 2015

Association between maternal urinary arsenic species and infant cord blood leptin levels in a New Hampshire Pregnancy Cohort.

Environ Res 2015 Jan 20;136:180-6. Epub 2014 Nov 20.

Institute of Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Children's Environmental Health & Disease Prevention Research Center at Dartmouth, Hanover, NH 03755, USA; Section of Biostatistics and Epidemiology, Department of Community and Family Medicine and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA. Electronic address:

Leptin is an important pleiotropic hormone involved in the regulation of nutrient intake and energy expenditure, and is known to influence body weight in infants and adults. High maternal levels of arsenic have been associated with reduced infant birth weight, but the mechanism of action is not yet understood. This study aimed to investigate the association between in utero arsenic exposure and infant cord blood leptin concentrations within 156 mother-infant pairs from the New Hampshire Birth Cohort Study (NHBCS) who were exposed to low to moderate levels of arsenic through well water and diet. In utero arsenic exposure was obtained from maternal second trimester urinary arsenic concentration, and plasma leptin levels were assessed through immunoassay. Results indicate that urinary arsenic species concentrations were predictive of infant cord blood leptin levels following adjustment for creatinine, infant birth weight for gestational age percentile, infant sex, maternal pregnancy-related weight gain, and maternal education level amongst 149 white mother-infant pairs in multivariate linear regression models. A doubling or 100% increase in total urinary arsenic concentration (iAs+MMA+DMA) was associated with a 10.3% (95% CI: 0.8-20.7%) increase in cord blood leptin levels. A 100% increase in either monomethylarsonic acid (MMA) or dimethylarsinic acid (DMA) was also associated with an 8.3% (95% CI: -1.0-18.6%) and 10.3% (95% CI: 1.2-20.2%) increase in cord blood leptin levels, respectively. The association between inorganic arsenic (iAs) and cord blood leptin was of similar magnitude and direction as other arsenic species (a 100% increase in iAs was associated with a 6.5% (95% CI: -3.4-17.5%) increase in cord blood leptin levels), albeit not significant. These results suggest in utero exposure to low levels of arsenic influences cord blood leptin concentration and presents a potential mechanism by which arsenic may impact early childhood growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2014.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262605PMC
January 2015

Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior.

Psychoneuroendocrinology 2015 Feb 10;52:32-42. Epub 2014 Nov 10.

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

Infant neurobehavior, a potential sentinel of future mental and behavioral morbidity characterized in part by reflex symmetry, excitability and habituation to stimuli, is influenced by aspects of the intrauterine environment partially through epigenetic alterations of genes involved in the stress response. DNA methylation of two related cortisol response genes, the glucocorticoid receptor (NR3C1), a nuclear receptor to which cortisol binds, and 11-beta hydroxysteroid dehydrogenase (HSD11B2), the enzyme responsible for conversion of cortisol into inactive cortisone, independently associate with infant neurobehavior. Although these factors are part of a common cortisol regulation pathway, the combined effect of DNA methylation of these factors on infant neurobehavior has not been characterized. Therefore, we conducted an examination of the joint contribution of NR3C1 and HSD11B2 DNA methylation on infant neurobehavior. Among 372 healthy term newborns, we tested the interaction between placental NR3C1 and HSD11B2 DNA methylation in association with neurobehavior as assessed with the validated NICU Network Neurobehavioral Scales. Controlling for confounders, interactions between DNA methylation of these genes were detected for distinct domains of neurobehavior (habituation, excitability, asymmetrical reflexes). Moreover, different patterns of DNA methylation across the cortisol regulation pathway associated with different neurobehavioral phenotypes. Those with low NR3C1 methylation but high HSD11B2 methylation had lower excitability scores; those with high NR3C1 methylation but low HSD11B2 methylation had more asymmetrical reflexes; those with high DNA methylation across the entire pathway had higher habituation scores. These results suggest that epigenetic alterations across the cortisol regulation pathway may contribute to different neurobehavioral phenotypes, likely though varying degrees of glucocorticoid exposure during gestation. While the postnatal environment may continue to affect neurobehavioral risk, this study provides novel insights into the molecular basis for fetal origins of mental conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psyneuen.2014.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350656PMC
February 2015

Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort.

PLoS One 2014 12;9(8):e104913. Epub 2014 Aug 12.

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America; Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104913PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130612PMC
April 2016

Epigenetic Regulation of Infant Neurobehavioral Outcomes.

Med Epigenet 2014 May;2(2):71-79

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, 7650 Remsen, Hanover, NH 03755, USA ; Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth and Norris Cotton Cancer Center, 1 Medical Center Drive, 7927 Rubin Building, Lebanon, NH 03756, USA.

During fetal development and early-infancy, environmental signals can induce epigenetic changes that alter neurobehavioral development and later-life mental health. Several neurodevelopmental genetic diseases influence epigenetic regulatory genes and genomic imprinting. Recently, brain epigenetic marks have been involved in idiopathic neurodevelopmental disorders including autism spectrum disorders (ASD). The placenta is an important regulator of the intrauterine environment that links maternal and fetal nervous systems. Placental epigenetic signatures have been associated with neurodevelopment of healthy newborns quantified through the NICU Network Neurobehavioral Scales (NNNS). Associations have been observed for DNA methylation of genes involved in cortisol (), serotonin (), and metabolic () pathways. Dysregulation of imprinted genes and microRNAs has also been associated with neurobehavior assessed by NNNS. Further analysis is needed to characterize the mechanisms by which the epigenome influences neurodevelopment, and the connection between this dysregulation and mental health disorders. In the future, epigenetic marks could serve as functional biomarkers of mental health and cognitive function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000361026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116357PMC
May 2014

Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation.

Am J Obstet Gynecol 2014 Dec 19;211(6):654.e1-9. Epub 2014 Jun 19.

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH; Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH. Electronic address:

Objective: In this study, we aimed to investigate relationships between maternal prepregnancy obesity and gestational diabetes mellitus and placental leptin DNA methylation.

Study Design: This study comprises data on 535 mother-infant dyads enrolled in the Rhode Island Child Health Study, a prospective cohort study of healthy term pregnancies. Prepregnancy body mass index was calculated from self-reported anthropometric measures and gestational diabetes mellitus diagnoses gathered from inpatient medical records. DNA methylation of the leptin promoter region was assessed in placental tissue collected at birth using quantitative bisulfite pyrosequencing.

Results: In a multivariable regression analysis adjusted for confounders, infants exposed to gestational diabetes mellitus had higher placental leptin methylation (β = 1.89, P = .04), as did those demonstrating prepregnancy obesity (β = 1.17, P = .06). Using a structural equations model, we observed that gestational diabetes mellitus is a mediator of the effects of prepregnancy obesity on placental leptin DNA methylation (β = 0.81, 95% confidence interval, 0.27-2.71).

Conclusion: Our results suggest that the maternal metabolic status before and during pregnancy can alter placental DNA methylation profile at birth and potentially contribute to metabolic programming of obesity and related conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2014.06.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254188PMC
December 2014
-->