From the Editor’s Desk
From a Contemporary Review on polyaromatic hydrocarbons and lung cancer to papers on regional vulnerability in the brain to PBPK modeling, this issue illustrates the breadth of our field. Following up on our discussions of reproducibility in toxicology, a Forum article details the steps being taken at the Environmental Protection Agency to improve their processes regarding reproducibility. This issue also features an editorial that addresses some of the challenges facing young investigators in toxicology. It can be exceedingly difficult to remain optimistic in a research climate that is under ongoing strain, but we must be careful of how our pessimism impacts the upcoming generation of toxicologists. We must focus on preparing our trainees to succeed in an uncertain future. The success of our field depends on how the next generation responds to these future challenges. As always, I encourage the readers to look inside ToxSci for the best original research in the field of toxicology. —Gary W. Miller
Editor’s Highlights
Testing of oligonucleotide toxicity
Oligonucleotides have long been used in the laboratory to manipulate gene expression due to their selectivity and specificity. Oligonucleotide-based approaches are now finding their way into the clinic. Phosphorothioate is commonly added to nucleotides to reduce their susceptibility to nucleases and enhance their therapeutic potential. One of the major safety concerns is that degradation of the modified oligos can lead to the release of modified monomeric nucleotides that disrupt normal DNA function. Specifically, mutation at the thymidine kinase locus is used to test for these potential dangerous cleavage products. The test involves induction of resistance to a particular selective marker. One oligo cleavage product, abbreviated dAMPαS, tests positive in this assay. Saleh and coworkers (pp. 169–176) demonstrate that while dAMPαS yields positive results in the assay, it does so through its effects on the cell cycle and altering resistance to the selective marker in the cell model, but does not actually act as a mutagen at the TK locus. These results suggest that current means of testing for the mutagenic effects of oligonucleotide-based therapeutics may not be accurately assessing the potential risk. View Abstract
Novel biomarker of acute renal injury
Reclamation of water and nutrients by the kidneys is essential for life. Many toxicants exert their effects within the kidney leading to reduced renal function. Monitoring damage to the kidney, especially before irreversible damage has occurred, is an important goal, as such there is an ongoing need to identify biomarkers of early toxicity. In this issue, Whitaker et al. (pp. 108–117) report that full-length ATP synthase subunit β is released into the urine shortly after ischemia-reperfusion injury in rats and this release is associated with mitochondrial damage within the kidney. Although ATP synthase subunit β is also released into the urine in the nonalcoholic steatohepatitis model, it is only the cleaved form. The research team then went on to demonstrate that in patients suffering from acute kidney injury following surgery that full-length ATP synthase subunit β was detectable in the urine. The identification and characterization of this biomarker in an established laboratory model as well as in human patients provides an excellent example of translational toxicology. View Abstract
Oxidative stress and nongenotoxic carcinogens
Carcinogens that do not exert direct mutagenic effects on DNA are referred to as nongenotoxic carcinogens. Many in this class are thought to exert their adverse actions via induction of oxidative stress, although there have not been strong data to support this. That said, this mechanism is commonly used to explain the actions of this class of carcinogens. In this issue, Henderson and colleagues (pp. 138–148) used a heme oxygenase reporter mouse to monitor induction of oxidative stress in the liver of mice exposed to a variety of carcinogens. The results revealed some striking inconsistencies, in that some nongenotoxic carcinogens did not appear to alter redox function. These findings lend caution to the presumption that all of these compounds are relying on perturbation of oxidative signaling to contribute to carcinogenesis. Although this article does not identify alternate explanations it does reveal a clear gap in knowledge, which should prompt a closer examination of this class of chemicals. View Abstract
Flame retardants in fish
The desire to prevent devastating injury due to fire had led to the production and use of a broad array of flame retardants, including those of the brominated and organophosphate classes. After decades of use the potential adverse effects on human health are beginning to be more closely examined. Noyes and colleagues (pp. 177–195) employed the embryonic zebrafish platform to test over 40 of these compounds for their ability to impair neurodevelopment. The high throughput nature of the approach allows for a battery of outcomes to be measured. Over 90% of the tested compounds showed adverse outcomes on one or more of the bioassays. More importantly, was that the approach was able to identify particular structural features that were associated with the adverse outcomes on the development of the nervous system. This structure-activity relationship data cannot only be used to identify other potentially toxic compounds but also, more importantly, lead to the development of safer alternatives. View Abstract