Genetic Modification of the Association between Peripubertal Dioxin Exposure and Pubertal Onset in a Cohort of Russian Boys
Olivier Humblet,1,2 Susan A. Korrick,1,3 Paige L. Williams,4 Oleg Sergeyev,5,6 Claude Emond,7 Linda S. Birnbaum,8 Jane S. Burns,1 Larisa M. Altshul,1,9 Donald G. Patterson Jr.,10 Wayman E. Turner,11 Mary M. Lee,12 Boris Revich,13 and Russ Hauser1
1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2Center for Health and Community, University of California–San Francisco, San Francisco, California, USA; 3Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; 4Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA; 5Department of Physical Education and Health, Samara State Medical University, Samara, Russia; 6Chapaevsk Medical Association, Chapaevsk, Russia; 7BioSimulation Consulting Inc., Newark, Delaware, USA; 8National Institute of Environmental Health Sciences/National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; 9Environmental Health and Engineering, Inc., Needham, Massachusetts, USA; 10EnviroSolutions Consulting, Inc., Jasper, Georgia, USA; 11Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 12Pediatric Endocrinology Division, Departments of Pediatrics and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA; 13Center for Demography and Human Ecology, Institute for Forecasting, Russian Academy of Sciences, Moscow, Russia
Background: Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes could provide insight into mechanistic pathways. This is one of the first studies to assess genetic susceptibility to dioxins.
Objectives: We evaluated whether common polymorphisms in genes affecting either molecular responses to dioxin exposure or pubertal onset influence the association between peripubertal serum dioxin concentration and male pubertal onset.
Methods: In this prospective cohort of Russian adolescent boys (n = 392), we assessed gene–environment interactions for 337 tagging single-nucleotide polymorphisms (SNPs) from 46 candidate genes and two intergenic regions. Dioxins were measured in the boys’ serum at age 8–9 years. Pubertal onset was based on testicular volume and on genitalia staging. Statistical approaches for controlling for multiple testing were used, both with and without prescreening for marginal genetic associations.
Results: After accounting for multiple testing, two tag SNPs in the glucocorticoid receptor (GR/NR3C1) gene and one in the estrogen receptor-α (ESR1) gene were significant (q < 0.2) modifiers of the association between peripubertal serum dioxin concentration and male pubertal onset defined by genitalia staging, although not by testicular volume. The results were sensitive to whether multiple comparison adjustment was applied to all gene–environment tests or only to those with marginal genetic associations.
Conclusions: Common genetic polymorphisms in the glucocorticoid receptor and estrogen receptor-α genes may modify the association between peripubertal serum dioxin concentration and pubertal onset. Further studies are warranted to confirm these findings.
Key words: children, development, gene–environment interaction, PCBs, puberty, TCDD.
Environ Health Perspect 121:111–117 (2013). http://dx.doi.org/10.1289/ehp.1205278 [Online 10 October 2012]
Address correspondence to R. Hauser, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Building I, Room 1405, Boston, MA 02115 USA. Telephone: (617) 432-3326. Fax (617) 432-0219. E-mail: email@example.com
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205278).
We thank colleagues M. Ter-Minassian and D. Poznick for advice on research methods.
This work was funded by grants from the U.S. Environmental Protection Agency (EPA R82943701) and the National Institute of Environmental Health Sciences (NIEHS) (ES014370, ES00002, and 5T32-ES07069-28). O.H. was supported by the Robert Wood Johnson Foundation Health & Society Scholars program and grant 5T32ES016645-02 from NIEHS/National Human Genome Research Institute. M.M.L. is a member of the University of Massachusetts Diabetes and Endocrinology Research Center (DK32520).
The research described in this article has been reviewed by the NIEHS, and approved for publication. Approval does not signify that the contents necessarily reflect the views of the Agency, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use. The opinions expressed in this manuscript are those of the authors and do not necessarily reflect the official opinion of the Centers for Disease Control and Prevention.
C.E. is the president of BioSimulation Consulting Inc. L.M.A. is a consultant for Environmental Health and Engineering, Inc. D.G.P. is a consultant for Axys Analytical Solutions, Fluid Management Systems, Inc., and Trium Environmental Solutions. The other authors declare they have no actual or potential competing financial interests.
Received 29 March 2012; Accepted 10 October 2012; Online 10 October 2012.
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