In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain.
Intrauterine exposure to maternal smoking is linked to impaired executive function and behavioral problems in the offspring. Maternal smoking is associated with reduced fetal brain growth and smaller volume of cortical gray matter in childhood, indicating that prenatal exposure to tobacco may impact cortical development and manifest as behavioral problems. Cellular development is mediated by changes in epigenetic modifications such as DNA methylation, which can be affected by exposure to tobacco.



In this study, we sought to ascertain how maternal smoking during pregnancy affects global DNA methylation profiles of the developing dorsolateral prefrontal cortex (DLPFC) during the second trimester of gestation. When DLPFC methylation profiles (assayed via Illumina, HM450) of smoking-exposed and unexposed fetuses were compared, no differentially methylated regions (DMRs) passed the false discovery correction (FDR ≤ 0.05). However, the most significant DMRs were hypomethylated CpG Islands within the promoter regions ofGNA15andSDHAP3of smoking-exposed fetuses. Interestingly, the developmental up-regulation ofSDHAP3mRNA was delayed in smoking-exposed fetuses. Interaction analysis between gestational age and smoking exposure identified significant DMRs annotated toSYCE3,C21orf56/LSS, SPAG1andRNU12/POLDIP3that passed FDR. Furthermore, utilizing established methods to estimate cell proportions by DNA methylation, we found that exposed DLPFC samples contained a lower proportion of neurons in samples from fetuses exposed to maternal smoking. We also show through in vitro experiments that nicotine impedes the differentiation of neurons independent of cell death.



We found evidence that intrauterine smoking exposure alters the developmental patterning of DNA methylation and gene expression and is associated with reduced mature neuronal content, effects that are likely driven by nicotine.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Medical Epigenetics, James J. Peters VA Medical Center, Bronx, NY 10468 USA.
Zac
Z
Chatterton
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.
Brigham J
BJ
Hartley
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.
Man-Ho
MH
Seok
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Medical Epigenetics, James J. Peters VA Medical Center, Bronx, NY 10468 USA.
Natalia
N
Mendelev
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Medical Epigenetics, James J. Peters VA Medical Center, Bronx, NY 10468 USA.
Sean
S
Chen
Department of Psychiatry, Columbia University, New York, NY 10032 USA.
Maria
M
Milekic
Department of Psychiatry, Columbia University, New York, NY 10032 USA.|Macedonian Academy of Sciences and Arts, Skopje, Macedonia.|School of Medicine, Skopje, Macedonia.
Gorazd
G
Rosoklija
School of Medicine, Skopje, Macedonia.
Aleksandar
A
Stankov
Psychiatric Hospital Skopje, Skopje, Macedonia.
Iskra
I
Trencevsja-Ivanovska
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.
Kristen
K
Brennand
Department of Neurology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.
Yongchao
Y
Ge
Department of Psychiatry, Columbia University, New York, NY 10032 USA.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032 USA.|Macedonian Academy of Sciences and Arts, Skopje, Macedonia.
Andrew J
AJ
Dwork
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029 USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Floor 10, Room 10-70D, New York, NY 10029 USA.|Medical Epigenetics, James J. Peters VA Medical Center, Bronx, NY 10468 USA.
Fatemeh
0000-0003-0920-6956
F
Haghighi
D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D047109:Fetal Development / Q000235:genetics; D005333:Fetus / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011401:Promoter Regions, Genetic; D012907:Smoking; D013385:Succinate Dehydrogenase / Q000235:genetics; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
C498585:TUBB3 protein, human; D014404:Tubulin; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; C112631:G protein alpha 16; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
Brain; DNA methylation; Epigenetics; Fetal; Neurodevelopment; Neuron; Nicotine; Prenatal; Smoking; Tobacco