Dose-dependent transitions in mechanisms of toxicity

Slikker, William; Andersen, Melvin E.; Bogdanffy, Matthew S.; Bus, James S.; Cohen, Steven D.; Conolly, Rory B.; David, Raymond M.; Doerrer, Nancy G.; Dorman, David C.; Gaylor, David W.; Hattis, Dale; Rogers, John M.; Setzer, R. Woodrow; Swenberg, James A.; Wallace, Kendall B.

doi:10.1016/j.taap.2004.06.019

Cited by 157 publications

(91 citation statements)

References 82 publications

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“…Our work also indicated that responses in the low-dose region could vary from superlinear to sublinear, and even to J-shaped curvatures, depending on the strength of homeostatic regulation. Overall, these changing responses are consistent with the socalled dose-dependent transition proposed for many chemical compounds [58,59].…”

Section: Discussionsupporting

confidence: 86%

Dose Response Relationship in Anti-Stress Gene Regulatory Networks

Zhang¹,

Andersen²

2005

PLoS Comput Biol

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To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O 2 , is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steadystate dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

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Section: Discussionsupporting

confidence: 86%

Dose Response Relationship in Anti-Stress Gene Regulatory Networks

Zhang¹,

Andersen²

2005

PLoS Comput Biol

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“…Actually, another relevant point should be addressed: the dosedependent transitions. A transition is a change with increasing dose in key underlying kinetic and/or dynamic factors that influence the mechanism responsible for the observed toxicity, resulting in a change in the relationship of the response rate as function of dose (Slikker et al, 2004a). The saturable or inducible factors such as absorption, distribution, elimination, metabolism, besides receptor interactions and altered homeostasis are the basis for dose-dependent transitions.…”

Section: Pesticidementioning

confidence: 99%

The problem of maternal toxicity in developmental toxicity studies

Giavini

Menegola

2012

Regulatory Toxicology and Pharmacology

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“…A CRITICAL DOSE LEVEL FOR RISK ASSESSMENT 247 significance of dose-dependent transitions has also more recently been discussed, and it has been argued that consideration of such transitions could improve the risk assessment (Slikker et al, 2004a(Slikker et al, , 2004b. For example, the identification of a transition dose region is suggested to be crucial to properly define the lowest range of doses appropriate for extrapolation, for example between different species.…”

Section: Discussionmentioning

confidence: 99%