Dissection of the hormetic curve: analysis of components and mechanisms

Abstract

The relationship between the dose of an effector and the biological response frequently is not described by a linear function and, moreover, in some cases the dose-response relationship may change from positive/adverse to adverse/positive with increasing dose. This complicated relationship is called "hormesis". This paper provides a short analysis of the concept along with a description of used approaches to characterize hormetic relationships. The whole hormetic curve can be divided into three zones: I - a lag-zone where no changes are observed with increasing dose; II - a zone where beneficial/adverse effects are observed, and III - a zone where the effects are opposite to those seen in zone II. Some approaches are proposed to analyze the molecular components involved in the development of the hormetic character of dose-response relationships with the use of specific genetic lines or inhibitors of regulatory pathways. The discussion is then extended to suggest a new parameter (half-width of the hormetic curve at zone II) for quantitative characterization of the hormetic curve. The problems limiting progress in the development of the hormesis concept such as low reproducibility and predictability may be solved, at least partly, by deciphering the molecular mechanisms underlying the hormetic dose-effect relationship.

Keywords: components; hormesis; mechanisms; reactive oxygen species.

FIGURE 1.

Dose-response relationships: (A) the linear model, (B) the threshold (linear) model, (C) the J-shaped model, and (D) the inverted U-shaped model, or inverted J-shaped model. The dashed line shows initial level of the response being measured (endpoint). Description in the text.

FIGURE 2.

“Classic” presentation of the dose-response hormetic curve. Abbreviations used: NOAEL – no observable adverse effect level – the dose of inducer where no observable effect is seen; ZEP – zero equivalent point. Description in the text.

FIGURE 3.

Two- (A) and three-component (B) curves demonstrating the components contributing to the total hormetic curve. Curve 1 – general hormetic dose-response; 2 – pure negative effects of the effector, and 3 – negative (suppressive) effects in the presence of operating defense mechanisms. Description in the text.

FIGURE 4.

“Idealized” hormetic curve to depict quantitative features of the hormetic relationship. Zones described are: I – lag zone – no observable effects at low effector doses, II – zone of beneficial/adverse effects, III – zone of changes opposite to zone II – zone of adverse/beneficial effects. Description in the text.