Theoretical Concepts

New scientific findings on these issues are emerging at an exponential rate. Central to these findings is a reformulation of the traditional dichotomy between nature and nurture (the gene vs. environment argument) in the causation of disease (Figure 1).

That which is 'nature' is based on genes, while 'nurture' comes from the environment, sensu latu. Functional status and disease linked to genes were previously perceived as completely determined by heredity. Diseases traditionally viewed as nonhereditary ('environmental') can be caused by a wide array of exposures, stressors, experiences, nutrition, and other lifestyle factors. Concern about environment's interaction with the genetic determination of disease and functional differences has focused traditionally upon two pathways: (1) high-dose chemical exposures causing mutations and thus alterations in the base sequence of genes, and (2) genetic variation among individuals leading some to be more susceptible than others to certain contaminants.

The study of endocrine disruption today is dramatically altering this historical conceptualization. A property linked to a gene is, rather than simply being a factor determined by inheritance, one that is vulnerable to environmental disruption, particularly by EDCs. This is because EDCs at low levels can act during development

Traditional

Heredity

Heredity

Genes

Environment Genes

Phenotype

What we become

Output of gene expression

Contaminant interference with gene expression

Environment Genes

Phenotype

What we become

Contaminant interference with gene expression

Environment

Phenotype

What we become

Figure 1 Contrasting traditional with new formulations of the interactions of genes and environment in the determination of phenotype. Traditionally, genetic diseases have been seen as determined by heredity. In the new formulation, genetic patterns of gene expression are vulnerable to disruption by environmental contaminants at multiple points in the sequence of steps that lead to gene expression, thereby rendering genetic diseases susceptible to modification by environmental factors.

to permanently interfere with gene expression and other cellular activities, resulting in abnormalities and disease that becomes apparent in adulthood . Thus, while some functional deficits and disease states are due to inherited mutations in genetic makeup, many diseases may also be associated with alterations in gene expression. These alterations relate to differential methylation of cytosine in the 5' region of the promoter (where the presence of methyl-cytosine leads to gene silencing) as well as changes in acetylation/methylation of histone proteins that determine whether genes are able to be activated by transcription factors. These chemical modifications of chromatin and DNA are referred to as 'epigenetic' changes and are now recognized as a major factor in the process of cell differentiation as well as the ontogeny of cancer, in contrast to classical mutations, which involve base deletions and substitutions.

Initially, the majority of research on EDCs focused on interference with gene activation by the hormone 17/3-estradiol (the most potent endogenous estrogen), and some initially assumed that endocrine disruptors were all environmental estrogens. In contrast to this assumption, it is now recognized that many EDCs can stimulate genes and other cellular processes that have nothing to do with estrogen. Thus, over the last decade, EDCs have been shown to disrupt many other endogenous hormonal signaling molecules, including virtually all steroid hormones that have been carefully tested, as well as thyroid, retinoid, leptin, some transcription factors, growth factors, and other molecules not traditionally classified as hormones. One recent study even documents interference with chemical signaling between two symbiotic organisms, the bacterium Rhizobium and its leguminaceous host. The presumption now is that any chemically mediated signaling system is vulnerable, in principle, to disruption by chemicals to which wildlife and humans are exposed in their daily lives. However, there are, in fact, many EDCs that do act via cellular mechanisms that mediate the response to estradiol, whereas other EDCs antagonize estradiol or block the synthesis of estradiol. Whether estrogenic and antiestro-genic EDCs remain the largest group of chemicals that interfere with the endocrine system remains to be determined.

Given the enormous potential for EDCs to interfere with gene expression, how many of the 80 000+ chemicals registered for commercial use has endocrine disrupting activity? The vast majority of chemicals have not been tested in even the most basic way. Far fewer have been tested for endocrine disrupting effects, particularly during embryonic development, the most vulnerable time in life.

Altered gene expression during organismal development can induce dramatic and irreversible changes in developmental outcomes. Known effects of EDCs range from structural changes to functional deficits. For example, alterations in the production of hormone receptors in tissues through the alteration in the expression of genes for these receptors have been shown in experiments with laboratory animals, and these changes can then lead to altered responses to hormonal stimulation throughout the remainder of life. This can, in turn, lead to altered (increased or decreased) susceptibility to contamination with hormonal activity. .

Altered gene expression and cellular signaling subsequent to development can cause transient changes, termed activational responses, or particularly through carcinogenesis, permanent detrimental effects. For example, lifetime exposure to estrogen is the best predictor of breast cancer in women, and exposure to EDCs that are 'environmental estrogens' could plausibly increase breast cancer risk. Thus, the impact of EDCs vary depending upon a variety of factors, including when in the life cycle of the organism exposure occurs, as well as the duration and amount of exposure. Until recently, the great importance of life stage, the very great vulnerability of the embryo, and the fact that consequences of fetal exposure could be entirely different from those seen from adult exposure had not been appreciated.

Collectively, these new data from studies of EDCs are forcing a series of conceptual shifts that undermine long-held assumptions underlying toxicological studies and the applications of results from these studies to developing public health standards.

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