DES can developmentally imprint genes by changing the pattern of DNA methylation

Gene imprinting in developmental toxicology :
a possible interface between physiology and pathology

2001 Study Overview

  1. Introduction
  2. Hormonal carcinogenesis
  3. Effects of diethylstilbestrol (DES)
  4. Estrogens and gene imprinting in carcinogenesis
  5. Regulation of imprinting
  6. Conclusions


Gene imprinting is an epigenetic mechanism for accomplishing persistent change in gene expression.

In this brief paper, we explore the mechanisms for imprinting genes and present data showing that the synthetic estrogen, diethylstilbestrol (DES) can developmentally imprint genes by changing the pattern of DNA methylation.

We further discuss the implications of this and other findings for non-mutagenic aspects of developmental toxicology, and suggest ways to use this concept in modifying in vitro screening for developmental toxicants.

Effects of diethylstilbestrol (DES)

Thus, we have studied the methylation pattern of the promoter of the lactoferrin gene in mice treated developmentally with DES (a treatment resulting in persistent expression of lactotransferrin and epithelial cancers in the uterus). The pattern of DNA methylation in developmentally treated mice was compared to those treated as adults (neither persistent gene expression, nor cancers are seen in the uterus after treatment as adults).

Five CpG sites available for methylation occur in a region upstream from the ERE (estrogen response element) in the mouse lactotransferrin promoter. In the developmentally estrogenized mouse, two sites remain unmethylated, while in the corresponding control, only one CpG site remains unmethylated. It has been shown previously that a one base pair change in methylation pattern can have a strong effect on expression of the gene.

Adult mice treated with the same dose of DES for the same time did not have a change in the DNA methylation pattern of the lactotransferrin gene. This is consistent with the inability of such treatment in the adult to persistently change expression of the gene.

The altered methylation pattern associated with estrogen treatment during differentiation of uterine epithelial cells provides a mechanism for irreversible expression of a normally reversible signal or provides one possible route for the change from epigenetic to genetic in hormonal carcinogenesis.



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