Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it w...

The function of the p53 tumor suppressor protein must be highly regulated because p53 can cause cell death and prevent tumorigenesis. In cultured cells, the p90 MDM2 protein blocks the transcriptional activation domain of p53 and also stimulates the degradation of p53. Here we provide the first conclusive demonstration that p90 MDM2 constitutively regulates p53 activity in homeostatic tissues. Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival. Phenotypic analyses revealed that both the transcriptional activation and apoptotic functions of p53 were increased in these mice. However, the level of p53 protein was not coordinately increased, suggesting that p90 MDM2 can inhibit the transcriptional activation and apoptotic functions of p53 in a manner independent of degradation. Cremediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90 MDM2 constitutively regulates both the activity and the level of p53 in homeostatic tissues. The observation that only a subset of tissues with activated p53 underwent apoptosis indicates that factors other than p90 MDM2 determine the physiological consequences of p53 activation. Furthermore, reduction of mdm2 in vivo resulted in radiosensitivity, highlighting the importance of mdm2 as a potential target for adjuvant cancer therapies.

The p53 inhibitor murine double-minute gene 2 (Mdm2) is a target for potential cancer therapies, however increased p53 function can be lethal. To directly address whether reduced Mdm2 function can inhibit tumorigenesis without causing detrimental side effects, we exploited a hypomorphic murine allele of mdm2 to compare the effects of decreased levels of Mdm2 and hence increased p53 activity on tumorigenesis and life span in mice. Here we report that mice with decreased levels of Mdm2 are resistant to tumor formation yet do not age prematurely, supporting the notion that Mdm2 is a promising target for cancer therapeutics.

A developmental role for the Ahr locus has been indicated by the observation that mice harboring a null allele display a portocaval vascular shunt throughout life. To define the ontogeny and determine the identity of this shunt, we developed a visualization approach in which three-dimensional (3D) images of the developing liver vasculature are generated from serial sections. Applying this 3D visualization approach at multiple developmental times allowed us to demonstrate that the portocaval shunt observed in Ahr-null mice is the remnant of an embryonic structure and is not acquired after birth. We observed that the shunt is found in late-stage wild-type embryos but closes during the first 48 h of postnatal life. In contrast, the same structure fails to close in Ahr-null mice and remains open throughout adulthood. The ontogeny of this shunt, along with its 3D position, allowed us to conclude that this shunt is a patent developmental structure known as the ductus venosus (DV). Upon searching for a physiological cause of the patent DV, we observed that during the first 48 h, most major hepatic veins, such as the portal and umbilical veins, normally decrease in diameter but do not change in Ahr-null mice. This observation suggests that failure of the DV to close may be the consequence of increased blood pressure or a failure in vasoconstriction in the developing liver.

The relationship between the mechanisms that control an organism's lifespan and its ability to respond to environmental challenges are poorly understood. In Caenorhabditis elegans, an insulin-like signaling pathway modulates lifespan and the innate immune response to bacterial pathogens via a common mechanism involving transcriptional regulation by the DAF-16/ FOXO transcription factor. The C. elegans germ line also modulates lifespan in a daf-16-dependent manner. Here, we show that the germ line controls the innate immune response of C. elegans somatic cells to two different Gram-negative bacteria. In contrast to the insulin-like signaling pathway, the germ line acts via distinct signaling pathways to control lifespan and innate immunity. Under standard nematode culture conditions, the germ line regulates innate immunity in parallel to a known p38 MAPK signaling pathway, via a daf-16-independent pathway. Our findings indicate that a complex regulatory network integrates inputs from insulin-like signaling, p38 MAPK signaling, and germ line stem cells to control innate immunity in C. elegans. We also confirm that innate immunity and lifespan in C. elegans are distinct processes, as nonoverlapping regulatory networks control survival in the presence of pathogenic and nonpathogenic bacteria. Finally, we demonstrate that the p38 MAPK pathway in C. elegans is activated to a similar extent by both pathogenic and nonpathogenic bacteria, suggesting that both can induce the nematode innate immune response.In Caenorhabditis elegans, inhibition of either daf-2 insulin/ IGF-1-like signaling or germ line proliferation increases nematode lifespan (1-4), increases resistance to environmental stress (1, 5-11), and increases nematode survival in the presence of pathogen (12)(13)(14). Insulin-like signaling also affects lifespan and stress resistance in Drosophila and rodents (15)(16)(17)(18)(19), and possibly in humans (20 -23), indicating that this pathway is evolutionarily conserved. The germ line, under some conditions, can also modulate lifespan in Drosophila (24). The germ line may also affect lifespan and stress resistance in mammals, as transplantation of young ovarian tissue into older mice can lengthen mouse lifespan (25), and postponement of menopause in mice delays some age-related health complications (26). Thus, the role of the germ line in the regulation of lifespan may also be evolutionarily conserved.Here, we show that the C. elegans germ line controls nematode resistance to two different Gram-negative bacterial pathogens, Pseudomonas aeruginosa and Serratia marcescens. However, unlike the case with daf-2, the effects of the germ line on lifespan and pathogen resistance are mediated by separate signaling pathways. While the FOXO family transcription factor DAF-16 is necessary for germ line-induced changes in lifespan (1, 2), daf-16 does not affect germ line-induced changes in innate immunity under standard nematode culture conditions. Our findings also indicate that the germ line acts in parallel to a p38 MAPK 2 ...

No abstract

Copper is an essential metal that is able to produce reactive oxygen species and induce intracellular oxidative stress. Several studies have examined the effects of excessive copper and oxidative stress in various organisms and tissues, but few address the molecular mechanisms by which copper affects transcription. Our results demonstrated that in COS-7 cells, copper treatment caused an increase in the binding of nuclear proteins to AP-1 and antioxidant response elements. The level of copperinducible nuclear protein binding was modulated by increasing or decreasing the level of intracellular oxidative stress. Copper exposure also led to an increase in the steady state levels of c-fos, c-jun, and c-myc mRNAs. Exposure to copper resulted in an increase in the levels of phosphorylation and activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 pathways. The activation of these pathways resulted in a concomitant increase in c-Jun phosphorylation. We investigated the hypothesis that copper-induced oxidative stress leads to the formation of stable lipid peroxidation by-products, which activate MAPK pathways; ultimately affecting transcription. While exposure did result in the production of HNE, the timing of the increased levels of proto-oncogene mRNA, phosphorylation of c-jun, and phosphorylation and activation of MAPKs, as well as the inability of the lipophilic antioxidant vitamin E to abrogate MAPK phosphorylation suggests that the formation of stable lipid peroxidation by-products may not be the primary mechanism by which copper activates MAKKs. These results further elucidate the effects of copper on signal transduction pathways to alter gene expression.

Improved understanding of the relationship between brain iron imbalance and protein aggregation is likely to help in the development of therapeutic strategies that can restore brain iron homeostasis and mitigate neurotoxicity.