Toxicological Sciences, Vol 48, 38-50, Copyright © 1999 by Society of Toxicology
ME Andersen and HA Barton
Some endocrine-active compounds (EACs) act as agonists or antagonists of
specific hormones and may interfere with cellular control processes that
regulate gene transcription. Many mechanisms controlling gene expression
are universal to organisms ranging from unicellular bacteria to more
complex plants and animals. One mechanism, coordinated control of batteries
of gene products, is critical in adaptation of bacteria to new environments
and for development and tissue differentiation in multi-cellular organisms.
To coordinately activate sets of genes, all living organisms have devised
molecular modules to permit transitions, or switching, between different
functional states over a small range of hormone concentration, and other
modules to stabilize the new state through homeostatic interactions. Both
switching and homeostasis are regulated by controlling concentrations of
hormone-receptor complexes. Molecular control processes for switching and
homeostasis are inherently nonlinear and often utilize autoregulatory
feedback loops. Among the biological processes contributing to switching
phenomena are receptor autoinduction, induction of enzymes for ligand
synthesis, mRNA stabilization/activation, and receptor polymerization. This
paper discusses a variety of molecular switches found in animal species,
devises simple quantitative models illustrating roles of specific molecular
interactions in creating switching modules, and outlines the impact of
these switching processes and other feedback loops for risk assessments
with EACs. Quantitative simulation modeling of these switching mechanisms
made it apparent that highly nonlinear dose- response curves for hormones
and EACs readily arise from interactions of several linear processes acting
in concert on a common control point. These nonlinear mechanisms involve
amplification of response, rather than multimeric molecular interactions as
in conventional Hill relationships.
ARTICLES
Biological regulation of receptor-hormone complex concentrations in relation to dose-response assessments for endocrine-active compounds
K. S. Crump Group, Inc., North Carolina 27709, USA. andersenme@aol.com
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