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Health and Human Services | Food
and Drug Administration | NCTR
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Endocrine disrupting compounds (EDC's) are chemicals that either mimic endogenous hormones, interfere with pharmacokinetics or act by other mechanisms. A comprehensive definition of endocrine disruptors, given in [Kavlock, 1996 #40] follows:
"An exogenous agent that interferes with the production, release, transport,
metabolism, binding, action or elimination of natural hormones in the body responsible
for the maintenance of homeostasis and the regulation of developmental processes."
This definition includes the general types of mechanisms for endocrine disruptors.
Such adverse effects as compromised reproductive fitness, functional or morphological
birth defects, cancer and altered immune functions, among others, have been
reported in the scientific press for wildlife, in vitro, and in vivo studies.
These findings have received considerable attention in the popular press, led
to government regulatory actions and expanded research in Europe, Asia and the
U.S. Many suspected endocrine disruptors (ED's) are high-volume, economically
important chemicals, a factor that magnifies the need for resolution of the
scientific issues [Kavlock, 1996 #40;
Government, 2001 #1724].
The estrogen, androgen and thyroid receptors are members of the nuclear receptor superfamily and are conserved across vertebrates [Glass, 1997 #442; Mangelsdorf, 1995 #249]. These proteins function as ligand-activated transcription factors, regulating synthesis of proteins in many tissues. Estrogens appear to be responsible for growth, differentiation, functioning, and toxicity in tissues primarily through estrogen receptor (ER) binding interactions. ER is promiscuous in terms of the structural diversity of ligands it will bind [Katzenellenbogen, 1995 #129].
Some ligands can bind to several different nuclear receptors. Also, despite the conservation of receptors, individual ligands induce expression of different biological responses in different species and tissues. This is thought to be due to different mechanisms at the chromatin/gene level. Additionally, a ligand may act as a full or partial agonist, or a full antagonist, a phenomena crucial to the design of hormonal therapeutics, such as raloxifene [Brzozowski, 1997 #11].
Available data support conjecture that an estrogen diffuses to the cell nucleus, binds non-covalently to the ER, dimerizes, and changes shape. The shape of the complex, in turn, enables attachment to one of a diverse number of potential DNA docking sites, termed estrogen response elements [Stancel, 1995 #322]. This attachment triggers the formation of a transcription complex, a cluster of co-activator proteins that fit around the receptor homodimer, and activates a specific gene. Thus, one crucial element for initiation of transcription by the ligand-receptor complex is successful recruitment of additional polypeptides, forming an ensemble with the right shape. Crystallographic evidence suggests that the long side chains of anti-estrogens, such as tamoxifen, prevent binding of the tissue specific co-activators to a hydrophobic cleft formed by helix 12 of the ligand binding domain (LBD). Interestingly, tamoxifen can act as an agonist in uterine tissue, which may have co-activators that can cope with the abnormally shaped receptors [Jordan, 1998 #564]. Raloxifene is a designer estrogen that acts as an agonist in bone and heart tissue, eliciting prophylactic good estrogen effects, but is an antagonist in breast and uterine tissue. Generally, such tissue specific action can be expected for any exogenous chemical as is seen for the endogenous hormones. Cells also manifest differential responses as a consequence of tissue-specific concentrations and ratios of receptor isoforms. These isoforms show similar responses for some ligands, and large differences for others [Kuiper, 1997 #45]. The structural features in the ligand binding domain causing the structural sensitivity between ER isoforms alpha and beta have been elucidated using QSAR methods [Tong, 1997 #174].
