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Review Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1408244

Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

Qiang Zhang,1 Sudin Bhattacharya,1 Rory B. Conolly,2 Harvey J. Clewell III,1 Norbert E. Kaminski,3 and Melvin E. Andersen1
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1Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA; 2Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Durham, North Carolina, USA; 3Department of Pharmacology & Toxicology and Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA
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This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell III HJ, Kaminski NE, Andersen ME. Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1408244.

Received: 7 February 2014
Accepted: 12 August 2014
Advance Publication: 12 August 2014

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Abstract

Background: Increasingly, there is a move toward using in vitro toxicity testing for assessment of human health risk by chemicals. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.

Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data.

Methods: Here we have examined dose-response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures.

Discussion and Conclusion: Integral feedback, feedforward and transcritical bifurcation motifs can generate thresholds. Other motifs, e.g., proportional feedback and ultrasensitivity, produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.


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