Environmental Exposure, DNA Methylation, and Gene Regulation
Lessons from Diethylstilbesterol-Induced Cancers
SHUANFANG LI
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA
Search for more papers by this authorSTEPHEN D. HURSTING
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA
Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, Bethesda, Maryland 20892, USA
Search for more papers by this authorBARBARA J. DAVIS
Laboratory of Women's Health, National Institute of Environmental Health Sciences, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA
Search for more papers by this authorJOHN A. McLACHLAN
Tulane/Xavier Center for Bioenvironmental Research, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA
Search for more papers by this authorCorresponding Author
J. CARL BARRETT
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA
Address for correspondence: J. Carl Barrett, Ph.D., Laboratory of Biosystems and Cancer, National Cancer Institute, National Institutes of Health, Bldg. 37, Rm. 5032, 9000 Rockville Pike, Bethesda, MD 20892. Voice: 301-594-8466; fax: 301-480-2772. [email protected]Search for more papers by this authorSHUANFANG LI
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA
Search for more papers by this authorSTEPHEN D. HURSTING
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA
Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, Bethesda, Maryland 20892, USA
Search for more papers by this authorBARBARA J. DAVIS
Laboratory of Women's Health, National Institute of Environmental Health Sciences, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA
Search for more papers by this authorJOHN A. McLACHLAN
Tulane/Xavier Center for Bioenvironmental Research, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA
Search for more papers by this authorCorresponding Author
J. CARL BARRETT
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA
Address for correspondence: J. Carl Barrett, Ph.D., Laboratory of Biosystems and Cancer, National Cancer Institute, National Institutes of Health, Bldg. 37, Rm. 5032, 9000 Rockville Pike, Bethesda, MD 20892. Voice: 301-594-8466; fax: 301-480-2772. [email protected]Search for more papers by this authorAbstract
Abstract: DNA methylation is an epigenetic mechanism that regulates chromosomal stability and gene expression. Abnormal DNA methylation patterns have been observed in many types of human tumors, including those of the breast, prostate, colon, thyroid, stomach, uterus, and cervix. We and others have shown that exposure to a wide variety of xenobiotics during critical periods of mammalian development can persistently alter the pattern of DNA methylation, resulting in potentially adverse biological effects such as aberrant gene expression. Thus, this epigenetic mechanism may underlie the observed increased risk in adulthood of several chronic diseases, including cancer, in response to xenobiotic exposures early in life. We present here the lessons learned from studies on the effects of perinatal diethylstilbesterol (DES) exposure on the methylation pattern of the promoters of several estrogen-responsive genes associated with the development of reproductive organs. Perinatal DES exposure, which induces epithelial tumors of the uterus in mice and is associated with several reproductive tract abnormalities and increased vaginal and cervical cancer risk in women, provides a clear example of how estrogenic xenobiotic exposure during a critical period of development can abnormally demethylate DNA sequences during organ development and possibly increase cancer risk later in life. In addition, nutritional factors and stress may also alter DNA methylation during early life and modulate the risk of cancer and other chronic diseases in adulthood. We suggest that DNA methylation status may be influenced by environmental exposures in early life, leading to increased risk of cancer in adulthood.
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