Environmental Exposure, DNA Methylation, and Gene Regulation

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.

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure

“…Supporters of the novel theory of fetal origins of adult disease are proposing that epigenetic changes such as DNA methylation and chromatin remodeling play a central role in carcinogenesis [50]. Ho and collaborators postulate that permanent alterations in the DNA methylation patterns of multiple cell signaling genes identified in the BPA-exposed prostates may be the underlying cause of neoplastic development later in life [47].…”

BRCA1 in hormonal carcinogenesis: basic and clinical research

“…Breast, endometrial, and prostate cancers are all known to be steroid hormone-responsive tumor types: the first two are estrogen-responsive, while the third is androgenresponsive. In addition, there is evidence supporting a role for estrogen in stimulating cell growth during the pathogenesis of cervical cancer in animal models and in humans (Elson et al 2000, Arbeit et al 2003, de Villiers 2003, Li et al 2003 although the hormonal etiology of cervical cancer is not as well established as in the other tumor types. BRCA2 mutations have been linked to ovarian, pancreatic, and prostatic cancers; but unlike BRCA1, BRCA2 mutations have not been linked to cervical and endometrial cancers (Streuwing et al 1997, Liede et al 2004, Lubinski et al 2004.…”

Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

“…Recent genomic approaches have identified thousands of genes that are aberrantly methylated in cancer, and associated with risk of recurrence and prognosis (2,3). Epigenetic changes could also be a biologic indicator of lifetime accumulation of environmental exposures related to early-life exposures (4), aging (5), hormones (6), alcohol (7), and smoking (8,9). Previously, it was thought that DNA methylation was a stable yet reversible modification (10).…”