Current Opinion in Toxicology最新文献

Radiation hormesis is generally described in terms of a narrow dose range over which radiation appears to result in beneficial effects before becoming harmful as the dose increases. We suggest in this article that a different way of looking at the issue might be profitable. In particular, we suggest that low-dose mechanisms have been clearly shown to be different to high-dose mechanisms and to involve activation of communication and signaling pathways. These have very low induction thresholds and saturate at doses within the range of interest making the concept of ‘dose’ rather irrelevant. We propose that instead of framing models, mechanisms and indeed radiation protection within a dose framework, we need instead to consider a response framework. In experimental studies, low-dose response or ‘effect’ is actually what we measure, for example, mutation, proteomic changes, oxidative stress, mitochondrial changes, etc. but we describe them as ‘surrogates’ for dose despite being aware of wide individual variations. Perhaps we need to accept that different doses will provoke different responses that will be context dependent. ‘Dose’ and ‘dose rate’ becomes ‘response’ and ‘response rate’, and would be determined by the type of communication signalling that was activated. Such a response model would allow factors such as age, sex, nutrition, genetics, epigenetics, and biochemical/biophysical functionality to be considered as determinants of outcome in addition to the physical dose deposition. We suggest that a more useful holistic understanding of hormesis should result.

Hormesis is a toxicological phenomenon whereby exposures to low doses of stress result in biological stimulation. The hormetic dose response is now recognized as a dominant response in toxicology occurring in a wide variety of organisms following exposure to numerous forms of stress. Here we briefly review recent research showing occurrences of hormesis in animals following exposure to frequently occurring and environmentally relevant contaminants/pollutants, including metals, industrial chemicals, pesticides, pharmaceuticals, and plastics. We also show evidence for underlying mechanisms for hormesis. We conclude by highlighting the importance of considering low-dose effects and hormesis when studying the consequences of environmental contamination/pollution.

The Earth was highly radioactive four billion years ago when life emerged. Even today, all humans are bombarded by 20,000 radiation strikes each second. Although high radiation doses are hazardous, organisms have evolved not only to tolerate lower-dose radiation but also to benefit by it (hormesis). Hormesis is prevailing in all species in various respects. An example is that hibakusha (Japanese A-bomb survivors) have longer lifespans and have lower risk of cancer, on average. Many microbes thrive in deep subsurface regions by consuming radiation as a source of nutrition. Low-dose radiation (LDR) is effective at treating severely affected COVID-19 patients, but the invalid linear no-threshold model (LNT) hinders the full beneficial use of LDR.

Recent studies have shown that alpha-ketoglutarate (AKG), an important cellular intermediate, prolongs lifespan and delays the onset of age-related decline in a dose-dependent manner in several model organisms such as nematodes, fruit flies, yeasts and mice. Mimicking a state of caloric restriction and acting as a hormesis-inducing agent are proposed to be possible mechanisms underlying lifespan-extending effects of dietary AKG. Here, we analyze potential molecular mechanisms by which AKG can imitate a state of caloric restriction and stimulate production of reactive oxygen species (ROS) in mitochondria. According to hormesis, moderate increase in ROS levels induces defensive mechanisms resulting in biologically beneficial effects, such as healthier and longer lifespan. Herewith, a strong oxidative stress by high AKG concentrations may be responsible for lifespan-shortening effects of this metabolite. Limitations of dietary restriction hypothesis as a mechanism of AKG action are also discussed.

Nephrotoxicity testing is an important step in preclinical development of new molecular entities (NMEs) and has traditionally been performed in 2D cell culture systems and animal models. However, 2D culture systems fail to replicate complex in vivo microenvironment and animal models face interspecies differences including the overexpression of drug transporters. In the last decade, 3D microphysiological systems (MPS) have been developed to address these concerns. Here, we review recent advancements in kidney MPS and their application in drug-induced toxicity testing and kidney disease research. We find that current research is making significant progress addressing MPS limitations such as throughput, incorporating various regions of the nephron such as the glomerulus, and successfully modeling and predicting clinically relevant nephrotoxicity of current and new drugs.

Misconceptions and misperceptions delayed the recognition of the importance of pesticide-induced hormesis in arthropods. Emphasis on lethality as an endpoint in experiments historically prevailed as sublethal effects were frequently neglected. This trend has shifted with the recognition of the importance of pesticide-induced hormesis, but with relatively passive evolution of the science, following a utilitarian view rooted mainly in agricultural pest management and crop yield. Direct pesticide effects on pest species remain the primary focus, which is now also directed to natural enemies of pest species and pollinators. This mini-review emphasizes how hormesis may affect species interactions and the broader consequences at the community level to provide further understanding of its eco-evolutionary relevance beyond its short-term practical implications for agriculture production.

Documented biphasic dose-responses date some 150 years back; however, massive evaluations of the occurrence of pollutant-induced hormesis, its quantitative characteristics, and the underlying mechanisms have been performed only in the recent years. One of the reasons why hormesis is not included in the ecological risk assessment may be its poorly explored relevance to levels of biological organization beyond the individual. Here, we summarize the highly reproducible occurrence of hormesis induced by various individual and combined chemicals in microorganisms, the hormetic response of bioluminescence, and the hormesis-based drug resistance. We also summarize key underlying mechanisms and discuss the relevance of hormesis in microorganisms-regulated organismic interactions, biological communication, and communities of microorganisms. Our exposition indicates the need for enhanced studies directed to reveal the implications of hormesis to levels of biological organization beyond the individual and that hormesis is considered in the ecological risk assessment.

Kidney is an excretion organ with influx transporters on the basolateral membrane of proximal tubular cells and efflux transporters on the apical membrane of proximal tubular cells. Cross-species differences in the expression, function, localization, and homology of kidney transporters are important considerations. Drug-indued kidney injury (DIKI) is mainly due to the intracellular drug accumulation or their metabolites and is associated with kidney histopathological changes and increase in serum creatinine (Scr). It is important to distinguish if an increase in Scr is related to DIKI or indirect inhibition of transporters leading to reversible and transient drug-induced Scr increase [DICI] without histopathological lesions. Finally, in vitro and in vivo animal models can predict unexpected changes in systemic exposure and kidney transporter-mediated effect.

The manipulation of oxygen to trigger the stimulatory response known as hormesis is an area of interest in insects that was born almost fifty years ago. Varying low-oxygen treatments have been investigated many times since with differing responses found; some hormetic/some harmful. In this review, we summarize the recent advancements in low-oxygen hormesis with a focus on severe hypoxia and anoxia. These two low-oxygen treatments fall below the critical partial oxygen pressure (PO₂, often referred to as P_crit), the oxygen level where metabolism is impaired, for insects and represent the most robust forms of this type of hormesis, yielding the largest protective responses recorded in insects. We introduce six factors that influence the effectiveness of low-oxygen hormesis: oxygen content, length of and age at treatment, treatment method, sex, and genetic background. Additionally, we present a glimpse at the known mechanism of this type of hormesis.

Hormesis in photosystem II (PSII) that is observed in appropriately planned studies is a dose or -time -response relationship to a disruption of homeostasis illustrated by U-shaped response curves. PSII that uses the light energy to oxidize water into molecular oxygen and delivers electrons and protons is more susceptible than photosystem I (PSI) to photodamage. A hormetic response of PSII is triggered by the non-photochemical fluorescence quenching (NPQ) mechanism that is a strategy to protect the photosynthetic apparatus from photo-oxidative damage by dissipating excess light energy as heat and preventing the destructive reactive oxygen species (ROS) creation. A basal level of ROS is needed for optimal plant growth, while a low increased level of ROS is beneficial for triggering hormetic responses, and a high level of ROS out of the boundaries is considered harmful to plants.