Environmental Agent Signaling

What Embryos and Evolution Teach Us About Endocrine Disrupting Chemicals

2001 Study Abstract

The term “endocrine disrupting chemicals” is commonly used to describe environmental agents that alter the endocrine system. Laboratories working in this emerging field—environmental endocrine research—have looked at chemicals that mimic or block endogenous vertebrate steroid hormones by interacting with the hormone’s receptor.

Environmental chemicals known to do this do so most often with receptors derived from the steroid/thyroid/retinoid gene family. They include ubiquitous and persistent organochlorines, as well as plasticizers, pharmaceuticals, and natural hormones. These chemicals function as estrogens, antiestrogens, and antiandrogens but have few, if any, structural similarities. Therefore, receptor-based or functional assays have the best chance of detecting putative biological activity of environmental chemicals. Three nuclear estrogen receptor forms—α, β, and γ—as well as multiple membrane forms and a possible mitochondrial form have been reported, suggesting a previously unknown diversity of signaling pathways available to estrogenic chemicals.

Examples of environmental or ambient estrogenization occur in laboratory experiments, zoo animals, domestic animals, wildlife, and humans. Environmentally estrogenized phenotypes may differ depending upon the time of exposure—i.e., whether the exposure occurred at a developmental (organizational and irreversible) or postdevelopmental (activational and reversible) stage. The term “estrogen” must be defined in each case, since steroidal estrogens differ among themselves and from synthetic or plant-derived chemicals.

An “estrogen-like function” seems to be an evolutionarily ancient signal that has been retained in a number of chemicals, some of which are vertebrate hormones. Signaling, required for symbiosis between plants and bacteria, may be viewed, therefore, as an early example of hormone cross-talk.

Developmental feminization at the structural or functional level is an emerging theme in species exposed, during embryonic or fetal life, to estrogenic compounds. Human experience as well as studies in experimental animals with the potent estrogen diethylstilbestrol provide informative models. Advances in the molecular genetics of sex differentiation in vertebrates facilitate mechanistic understanding. Experiments addressing the concept of gene imprinting or induction of epigenetic memory by estrogen or other hormones suggest a link to persistent, heritable phenotypic changes seen after developmental estrogenization, independent of mutagenesis.

Environmental endocrine science provides a new context in which to examine the informational content of ecosystem-wide communication networks. As common features come to light, this research may allow us to predict environmentally induced alterations in internal signaling systems of vertebrates and some invertebrates and eventually to explicate environmental contributions to human reproductive and developmental health.

Müllerian duct retention

The molecular mechanism for Müllerian duct retention associated with DES is becoming clearer. While it had been shown that the effect of DES on Müllerian duct retention resides at the level of the duct rather than the fetal testis (163), the molecular alteration in the duct has recently been shown to be a failure of the MIS receptor in the fetal duct to respond to the peptide. The molecular mechanisms associated with Müllerian pathogenesis after prenatal exposure to DES is starting to be understood. Ma et al. studied the localization of the Hox genes related to morphogenesis of the fetal Müllerian duct in the mouse. By concentrating on Hoxa, they determined the longitudinal distribution of these genes along the developing genital tract and were able to relate changes seen in Hoxa-10 gene disruption to that seen in prenatal exposure to DES.

Molecular feminization of the developmentally estrogenized male tissues

When the seminal vesicles of prenatally DES-exposed males were analyzed, lactotransferrin mRNA was detected. The level of expressed lactotransferrin message increased after castration of the male and exceeded that of the uterus when each was estrogen stimulated. These results comprise the first demonstration of hormonally altered sexual development at the gene level. Further analysis of the seminal vesicles of DES-treated mice demonstrated that while they retained the cytoarchitecture associated with the male organ, they expressed epithelial gene products associated with the uterus, i.e., lactotransferrin and ERα. In fact, virtually all the cells of the DES-exposed mouse seminal vesicle epithelium express antigens recognized by antisera to lactotransferrin and ERα.

Additional experiments were conducted to assess whether prenatal exposure to DES had feminized the seminal vesicle cells or, alternatively, blocked the masculinization of the organ at the molecular level. It was shown that DES-exposed mouse seminal vesicles were competent to express the seminal vesicle specific protein SVS-IV under androgen control as well as lactotransferrin. In fact, the same cell was often able to make both products.



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