Abstract

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N = 33; 16 smoking-exposed) as well as adult (N = 207; 57 active smokers) human postmortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)—these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.

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Acknowledgements

SAS, LCT, CAM, ADS, LJB, BSM, EOJ, DBH, and AEJ were supported by R01DA042090.

Author contributions

SAS: performed analyses and led the writing of the manuscript. LCT: performed analyses and contributed to the writing of the manuscript. CAM, LJB, BSM, and EOJ: contributed to the interpretation of the results and writing of the manuscript. JHS: performed data generation. ADS: performed clinical reviews and oversaw the assessment of toxicology. RT: performed RNA extractions. MAH: generated nicotine and cotinine data. TMH: performed tissue dissections, contributed to the study design, interpretation of the results, and writing of the manuscript. DRW: contributed to the study design, interpretation of the results, and writing of the manuscript. DBH: contributed to the study design, statistical analyses, interpretation of the results, and writing of the manuscript. JEK and AEJ: co-led the study, including the design, statistical analyses, interpretation, and writing of the manuscript.

Author information

Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA

    • Stephen A. Semick
    • , Leonardo Collado-Torres
    • , Joo Heon Shin
    • , Amy Deep-Soboslay
    • , Ran Tao
    • , Thomas M. Hyde
    • , Daniel R. Weinberger
    • , Joel E. Kleinman
    •  & Andrew E. Jaffe
  2. Center for Computational Biology, Johns Hopkins University, Baltimore, MD, 21205, USA

    • Leonardo Collado-Torres
    •  & Andrew E. Jaffe
  3. Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park 3040 East Cornwallis Road, NC, 27709, USA

    • Christina A. Markunas
    •  & Dana B. Hancock
  4. The Lambert Center for the Study of Medicinal Cannabis and Hemp, Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, USA

    • Marilyn A. Huestis
  5. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA

    • Laura J. Bierut
  6. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA

    • Brion S. Maher
    •  & Andrew E. Jaffe
  7. Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park 3040 East Cornwallis Road, NC, 27709, USA

    • Eric O. Johnson
  8. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    • Thomas M. Hyde
    • , Daniel R. Weinberger
    •  & Joel E. Kleinman
  9. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    • Thomas M. Hyde
    •  & Daniel R. Weinberger
  10. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    • Daniel R. Weinberger
  11. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    • Daniel R. Weinberger
    •  & Andrew E. Jaffe
  12. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA

    • Andrew E. Jaffe

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The authors declare that they have no conflict of interest.

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Correspondence to Joel E. Kleinman or Andrew E. Jaffe.

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https://doi.org/10.1038/s41380-018-0223-1