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David R. Colquhoun,¹ Lynn R. Goldman,¹ Robert N. Cole,² Marjan Gucek,² Malini Mansharamani,² Frank R. Witter,³ Benjamin J. Apelberg,⁴ and Rolf U. Halden^1,5

¹Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; ²Mass Spectrometry and Proteomics Facility, Institute for Basic Biomedical Sciences, and ³Department of Gynecology and Obstetrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA; ⁴Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; ⁵Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, Tempe, Arizona, USA

Abstract
Background: Exposures of pregnant women to natural and manmade chemicals can lead to negative health effects in the baby, ranging from low birth weight to developmental defects. In some cases, diseases were postulated to have their basis in toxic exposure in utero or in early childhood. Therefore, an understanding of fetal responses to environmental exposures is essential. To that end, cord blood is a readily accessible biofluid whose proteomic makeup remains mostly unexplored when compared with that of adults.

Objectives: Our goal was an initial global assessment of the fetal serum proteome and for the identification of protein biomarkers indicative of toxic in utero exposures related to maternal cigarette smoking.

Methods: Drawing from a repository of 300 samples, we selected umbilical cord blood sera from 12 babies born to six smokers and six nonsmokers and analyzed both sample pools by tandem mass spectrometry in conjunction with isobaric tags (iTRAQ) for protein quantification.

Results: We identified 203 proteins, 17 of which were differentially expressed between the cigarette smoke–exposed and control populations. Most of the identified candidate biomarkers were biologically plausible, thereby underscoring the feasibility of screening neonates with global proteomic techniques for biomarkers of exposure and early biological effects triggered by in utero chemical exposures.

Conclusions: This validation study provides an initial view of the proteome of human cord blood sera ; it demonstrates the feasibility of identifying therein by use of proteomics, biomarkers of environmental, toxic exposures.

Key words: cigarette smoke, comparative proteomics, iTRAQ, umbilical cord, serum. Environ Health Perspect 117:832–838 (2009) . doi:10.1289/ehp.11816 available via http://dx.doi.org/ [Online 2 December 2008]

Address correspondence to R. Halden, Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave., Mail Stop 875701, Tempe, AZ 85287-5701 USA. Telephone: (480) 727-0893. Fax: (480) 727-0889. E-mail: halden@asu.edu

Supplemental Material is available online at http://www.ehponline.org/members/2008/11816/suppl.pdf

We thank J. Bernert for performing the cotinine analyses and for reviewing the draft manuscript, L. Needham for helpful comments and administrative support of this study, J. Herbstman and J. Heidler for data and umbilical cord sample collection, J. Jasken and T. Young for manuscript review and assistance, and R. Quinn for study coordination.

This research was supported in part by the Maryland Cigarette Restitution Program Research Grant given to the Johns Hopkins Medical Institutions and by funding from the National Institute for Occupational Safety and Health Education and Research Center for Occupational Safety and Health at the Johns Hopkins Bloomberg School of Public Health (#T42CCT310419) . Development of the proteomic techniques was supported in part by the National Institute of Environmental Health Sciences grant 1R01ES015445. D.R.C. was supported by an ERC Biomarkers of Occupational Exposure and Susceptibility Training Grant.

R.U.H., D.R.C., L.R.G., and F.R.W. are listed as inventors on a provisional patent application relating to the use of identified proteins and biomarkers for diagnostic purposes. The other authors declare they have no competing financial interests.

Received 17 June 2008 ; accepted 2 December 2008.