Nicotine and Its Downstream Metabolites in Maternal and Cord Sera: Biomarkers of Prenatal Smoking Exposure Associated with Offspring DNA Methylation

Abstract

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.

Faktor Risiko Kejadian Bayi Berat Lahir Rendah (BBLR) di RSUD Lakipadada Kabupaten Tana Toraja

“…Keterpaparan asap rokok terhadap ibu yang sedang hamil sangat berpengaruh bagi janin yang dikandungnya dan dapat mengakibatkan bayi berat lahir rendah (BBLR) serta dapat mengakibatkan KJDR karena asap rokok yang dihirup oleh ibu hamil mengandung bahan kimia beracun antara lain, karbonmonoksida (CO) yang dihasilkan oleh asap rokok. Nikotin dalam asap rokok dicurigai sebagai neutrogen terhadap janin (23).…”

Maternal Secondhand Smoke Exposure Enhances Macrosomia Risk Among Pregnant Women Exposed to PM2.5: A New Interaction of Two Air Pollutants in a Nationwide Cohort

“…Secondly, studies on the association of PM 2.5 air pollutants and newborn birth weight outcomes suggested that the changes of oxidative stress ( 43 ), immune response ( 44 ), and epigenetic regulation ( 45 ) may influence birth weight. Furthermore, studies on the association of maternal tobacco smoke exposure and fetal birth weight suggested that placental toxicity ( 46 ) and epigenetic modifications, such as DNA methylation ( 47 ), could be potential mediators affecting fetal birth weight outcomes. So epigenetic modification could be an explanation for the interaction between maternal exposure to SHS and PM 2.5 air pollutants on the risk of macrosomia.…”

Fucoxanthin levels in maternal serum at birth and eczema risk in offspring in early childhood: A birth cohort study

“…Maternal blood samples were collected at the child's birth (predelivery) and were analyzed to measure metabolites, nutrients, and toxins (MNTs) using a data‐independent untargeted approach based on high‐resolution mass spectrometry coupled to varied sample introduction strategies (reversed‐phase liquid chromatography, hydrophilic interaction liquid chromatography, and flow‐injection analysis). Such an approached enabled a blind molecular profiling that does not require a priori knowledge of compound identities and is suitable for detecting a wide range of substances derived from environment, food, gut microbiome, and endogenous exposures 18,19 . Fucoxanthinol 3‐arachidate (nlp16.65_955.6949m_z) was measured using negative‐ion LC/high resolution MS on a Waters Xevo G2‐XS QTof mass spectrometer as its formate adduct ([M + formate] − ) as a continuous variable generated by the Progenesis QI software.…”

“…Such an approached enabled a blind molecular profiling that does not require a priori knowledge of compound identities and is suitable for detecting a wide range of substances derived from environment, food, gut microbiome, and endogenous exposures. 18,19 Fucoxanthinol 3-arachidate (nlp16.65_955.6949m_z) was measured using negative-ion LC/high resolution MS on a Waters Xevo G2-XS QTof mass spectrometer as its formate adduct ([M + formate] − ) as a continuous variable generated by the Progenesis QI software.…”