A biomarker‐based study of prenatal smoking exposure and autism in a Finnish national birth cohort

Nicotine is a major constituent of cigarette smoke. Its primary metabolite in maternal and cord sera, cotinine, is considered a biomarker of prenatal smoking. Nicotine and cotinine half-lives are decreased in pregnancy due to their increased rate of metabolism and conversion to downstream metabolites such as norcotinine and 3-hydroxycotinine. Hence, downstream metabolites of nicotine may provide informative biomarkers of prenatal smoking. In this study of three generations (F0-mothers, F1-offspring who became mothers, and F2-offspring), we present a biochemical assessment of prenatal smoking exposure based on maternal and cord sera levels of nicotine, cotinine, norcotinine, and 3-hydroxycotinine. As potential markers of early effects of prenatal smoking, associations with differential DNA methylation (DNAm) in the F1- and F2-offspring were assessed. All metabolites in maternal and cord sera were associated with self-reported prenatal smoking, except for nicotine. We compared maternal self-report of smoking in pregnancy to biochemical evidence of prenatal smoking exposure. Self-report of F0-mothers of F1 in 1989–1990 had more accuracy identifying prenatal smoking related to maternal metabolites in maternal serum (sensitivity = 94.6%, specificity = 86.9%) compared to self-reports of F1-mothers of F2 (2010–2016) associated with cord serum markers (sensitivity = 66.7%, specificity = 78.8%). Nicotine levels in sera showed no significant association with any DNAm site previously linked to maternal smoking. Its downstream metabolites, however, were associated with DNAm sites located on the MYO1G, AHRR, and GFI1 genes. In conclusion, cotinine, norcotinine, and 3-hydroxycotinine in maternal and cord sera provide informative biomarkers and should be considered when assessing prenatal smoking. The observed association of offspring DNAm with metabolites, except for nicotine, may imply that the toxic effects of prenatal nicotine exposure are exerted by downstream metabolites, rather than nicotine. If differential DNA methylation on the MYO1G, AHRR, and GFI1 genes transmit adverse effects of prenatal nicotine exposure to the child, there is a need to investigate whether preventing changes in DNA methylation by reducing the metabolic rate of nicotine and conversion to harmful metabolites may protect exposed children.

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Epigenetic signatures of smoking associate with cognitive function, brain structure, and mental and physical health outcomes in the Lothian Birth Cohort 1936

Translational Psychiatry ◽

10.1038/s41398-019-0576-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Janie Corley ◽

Simon R. Cox ◽

Sarah E. Harris ◽

Maria Valdéz Hernandez ◽

Susana Muñoz Maniega ◽

...

Keyword(s):

Dna Methylation ◽

Cognitive Function ◽

Health Outcomes ◽

Physical Health ◽

Birth Cohort ◽

Smoking Status ◽

Brain Mri ◽

Smoking Exposure ◽

Eta Squared ◽

Lothian Birth Cohort

Abstract Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n = 532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P < 0.001, eta-squared ɳ2 = 0.63) and smoking pack years (r = 0.69, P < 0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P < 0.001, partial eta-squared ɳp2 = 0.022) and processing speed (P < 0.001, ɳp2 = 0.030); inflammatory markers (all P < 0.001, ranges from ɳp2 = 0.021 to 0.030); dietary patterns (healthy diet (P < 0.001, ɳp2 = 0.052) and traditional diet (P < 0.001, ɳp2 = 0.032); stroke (P = 0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P < 0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P < 0.001, ranges from ɳp2 = 0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.

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Differential DNA Methylation in Purified Human Cord and Peripheral Blood: Biomarkers of Prenatal Smoking and Allergy in Children

Inquiry@Queen's Undergraduate Research Conference Proceedings ◽

10.24908/iqurcp.11555 ◽

2018 ◽

Author(s):

Lydia Noureldin

Keyword(s):

Birth Cohort ◽

Peripheral Blood ◽

Atopic Disease ◽

Accurate Method ◽

Statistical Testing ◽

Birth Cohort Study ◽

Prenatal Smoking ◽

World Population ◽

Skin Prick Tests ◽

Potential Biomarkers

Adjusting for nonresponse, 7.7% of Canadian adults suffer from allergies. On a broader scale, Allergic rhinitis affects approximately 10 – 25% of the world population. The study analyzed data (n=185) from the Kingston Allergy Birth Cohort study, a prospective birth cohort that has recruited over 300 pregnant women to date. A skin prick tests was administered to each child to quantify the phenotype, allergies, on a binary scale. Surveys filled out by the mothers revealed that 28% engaged in prenatal smoking, the highest rate in Ontario. Methylation in the human genome is known to be associated with development and disease. The study defines the methylome as the set of nucleic acid methylation modifications in a subject’s genome. With the Infinium MethylationEPIC BeadChip, the study collected DNA samples and examined over 850,000 methylation sites quantitatively across the genome at single-nucleotideresolution, to investigate the effects of allergies, and maternal smoking, on the methylome. Pre–processing steps including quality control, normalisation, data exploration, non-specific filtering, and statistical testing for probe-wise differential methylation was applied. After pre-processing and outlier removal, umbilical cord blood (n=50) and peripheral blood (n=70) was analyzed from the subjects. The study found differentially methylated sites that represent potential biomarkers that could be predictive of future atopic disease in childhood. These potential biomarkers may also serve as a more accurate method, than surveys filled out by the mothers which are susceptible to patient bias, in determining if a child was subject to prenatal smoking.

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