Persistent exposure to environmental heat stress upregulates protective mechanisms, leading to enhanced endurance during exposure to severe heat stress. This process is defined as 'heat acclimation'. It also leads to the generation of non-thermoregulatory beneficial effects displayed by increased tolerance to a multitude of environmental stressors, such as heavy metals, ischemia, hypoxia, ionized irradiation, etc. The latter protective feature is defined as 'cross-tolerance' (against these stressors). Our data on mammalian species indicate that reprogrammed gene expression, among which are genes coding for heat shock proteins (HSP 70 family) and energy metabolism enzymes leading to decreased heat production, plays a major role. Unfortunately, our knowledge of the "architecture" of acclimatory signaling in mammals is limited. Several previous studies reported on the ability of C. elegans to undergo heat acclimation. The relative ease of genetic and molecular manipulations in C. elegans makes this phylogenetically distant (from mammals) species worthwhile for addressing questions pertaining to mammalian biology. In the present study we aimed to characterize a C. elegans heat-acclimation model, to substantiate the generation of 'cross tolerance' in this model, and to identify selective pathways involved in the evolving adaptive responses. Heat-acclimated wild-type C. elegans (grown at 25degC for 24 or 96 hrs) had significantly increased heat endurance during exposure to heat stress at 35degC, and upon subjection to progressively increasing cadmium concentrations compared to that of normothermic worms (grown at 20degC). Heat acclimation in the wild type (N2) worms also produced 'cross tolerance' against chemical hypoxia (azide toxication). To identify the mediating signaling pathways, we examined two candidate pathways: the
daf-16 (insulin receptor pathway, known to affect stress and thermotolerance response), and the
hif-1 (hypoxia inducible factor, affecting metabolic pathways). LD50 of
daf-16 and
hif-1 knockout worms during exposure to 35degC, before and after heat acclimation, was measured. Our data showed that while the wild-type N2 and
daf-16 mutants showed enhanced heat endurance following the acclimation procedure, the
hif-1 knockout worm, although it performed better under normothermic conditions, could not acclimate, and long-term exposure at 25degC interfered with thermotolerance during the heat stress. These findings pinpoint unequivocally the importance of HIF-1 signaling in the acclimation process, and are in conformation with our data from rats that HIF-1 alpha is elevated following heat acclimation (Maloyan, Semenza, Gerstenblith, Stern Horowitz 20011). This may suggest that HIF-1's role in heat acclimation is conserved through evolution. 1 Maloyan,A., Semenza,G., Gerstenblith,G., Stern, M., Horowitz, M. Heat acclimation-ischemia cross-tolerance: Does HIF 1alpha play a role. ISHR 2001