Endocrine-Disrupting Pesticides - Pesticides: Evaluation of Environmental Pollution - page 613

20.5.2 Receptor
A receptor is usually a protein that selectively binds a chemical signal (ligand). The bind-
ing of an endogenous ligand leads to a specific cell response. The binding of a hormone-
disrupting substance with a receptor can activate the receptor in the same way as an
endogenous ligand, or it may interfere with the binding and action of endogenous ligands
without activating the receptor itself.
The result of a biological ligand-receptor interaction depends on many factors besides
the concentration of the ligand and the binding affinity of the chemical. Cell responses will
be different depending on the receptor types and transduction (transmission of signals or
genetic material) mechanisms in the cell and also on whether the ligand acts as a receptor
agonist, antagonist, inverse agonist, partial agonist, or gives a mixed response. An agonist
may activate a receptor resulting in a maximum response. Most natural ligands are ago-
nists. Antagonists bind to the receptor but do not activate it. The receptor is blocked from
binding of agonists. Inverse agonists are antagonists that further reduce the activation of
the receptor. Partial agonists activate the receptor not fully, and the biological response is
only partial.
Hormone disruption is a consequence of the binding of a hormone to its receptor on
the cell surface, cytoplasm, or nucleus. This is followed by a series of events that lead to
changes in gene expression. There are very few data available on the link between the
whole range of events and the adverse health effects including cancer and reproductive
disorders.
20.6 Endocrine Disruption
The mechanisms behind endocrine disruptors are very diverse.
To start, we must not forget that endogenous hormones act themselves through different
mechanisms. The classic mechanism of action of hormones, such as estrogens, androgens,
thyroid hormones, and progesterone, is a binding of the hormone to its receptor, the inter-
action of this hormone-receptor complex with other cofactors in the cell, and the activation
or inactivation of transcription of a gene.
Hormone receptors can also bind to chemicals (xenobiotics) other than the normal body
chemicals. An important note is in order here: a single hormone, such as estradiol, triggers
a whole variety of receptors, signaling mechanisms, and may interact with completely
different cofactors depending on the phenotype of the target cell. Furthermore, specific
enzymes are involved through synthesis, degradation, and inactivation of hormones.
A single, several, or all of these enzymes may be targets of endocrine disruptors.
Endogenous hormones, especially estrogen, androgen, and thyroid hormone, bind to
proteins in the blood which reduces their bioavailability. EDCs do not bind to the same pro-
tein which increases their bioavailability with respect to endogenous hormones. Enzymes
that break down endogenous hormones do not break down EDCs not always even quickly.
So they remain available for a longer duration and can be stored in reserve tissues, usually
fat, because most EDCs are fat-soluble.
There are other mechanisms of disruption of the system and functioning of steroid
hormones. Since very low doses of EDCs may have an adverse effect, traditional dose-
response curves are not applicable. The question raises here if thresholds for EDCs are
rightly in place. Exposure is usually for several endocrine disruptors, not for one. One