From the Editor’s Desk

In this issue’s editorial I address the topic of preprints in toxicology. Although a mainstay in physics for decades, the biomedical research community is still in the early phases of adoption. At Toxicological Sciences we strive to publish the highest quality research in the field. We focus on the point of submission to online publication, but efforts to improve the reporting of research results before and after that span are more than welcome. Preprints represent one of those possible strategies. I look forward to your feedback and encourage you to Look Inside ToxSci for the best original research in the field of toxicology.—Gary W. Miller

Editor’s Highlights

CCR2 and ozone-mediated lung injury

Following on the heels of recent work demonstrating a role for the angiotensin 1 receptor (AT1R) on splenic macrophages recruited to the lung after ozone exposure, Francis and colleagues (pp. 474) demonstrate a mechanistic role for the CCR2 receptor. CCR2 is the receptor for monocyte chemotactic protein-1 (MCP-1; CCL2), which is essential for recruitment of inflammatory cells. In the present study, wildtype and CCR2-knockout mice were exposed acutely to ozone, and detailed immunohistological and flow cytometric analyses confirmed that the knockout mice displayed blunted infiltration and pulmonary injury. The study further implicates these proinflammatory macrophages as arising from the bone marrow. These findings complement the recent discovery that the AT1R-expressing pro-inflammatory macrophages are derived from splenic stores following ozone exposure. Delineating the specific macrophage cell types and origins provides an important framework for future studies of factors of susceptibility, such as genetics or diet, in determining the pathological response to acute ozone exposure. View Abstract—Matthew J. Campen

Chromium VI exposure and the placenta

Chromium VI (CrVI) is used in numerous leather, textile, metallurgical, chemical, and automobile industries. Environmental CrVI exposure is associated with an increased risk of spontaneous abortion, stillbirth, preterm birth, and neonatal death. These associations may be due, in part, to the ability of CrVI to accumulate in the placenta and cause oxidative stress. Banu and coworkers recently determined that maternal exposure to CrVI during early pregnancy causes an anti-oxidant imbalance, resulting in reduction of the trophoblast population in the placenta. Specifically, the authors demonstrated that CrVI exposure decreased endovascular and interstitial trophoblast cell populations, expression of cell-specific markers for trophoblast cells, and expression of the cell division marker cyclin D1 in the placenta compared to controls. The authors also showed that CrVI exposure altered the spatial expression patterns of anti-oxidant proteins (Gpx1, Sod1, Sod2, Prdx-3, and Txn-2) in the placenta. Collectively, these findings indicate that CrVI exposure during early pregnancy may lead to adverse pregnancy outcomes by altering expression of anti-oxidant proteins and interfering with trophoblast proliferation in the placenta. View Abstract—Jodi A. Flaws

Interactions between buprenorphine and ethanol revealed

Buprenorphine (BUP), a semi-synthetic opioid, is widely used as an effective maintenance therapy in heroin addicts. BUP is safer than other opioids and exhibits a ceiling effect with regards to respiratory depression (ie, increased doses do not worsen the effect). Nevertheless, fatalities have occurred, especially after concomitant intake of ethanol or benzodiazepines. In these fatalities, BUP concentrations are generally within the therapeutic range. A combination of BUP and naloxone (NLX, an opioid antagonist) has been proposed but the effectiveness in overdose is unclear. The authors investigated the pharmacokinetics, sedation and respiratory depression in rats co-exposed to BUP or BUP + NLX intravenously and ethanol by gavage. In a second step, they tested the efficacy of NLX and flumazenil (FLZ, a benzodiazepine antagonist) as antidotes following ethanol + BUP intoxication. The authors found that BUP and ethanol combined results in neurorespiratory depression as a result of increased norbuprenorphine production. The depression was less pronounced after administration of BUP + NLX and ethanol. FLZ and NLX were not effective as antidotes after the combined exposure. This study represents a first step to understand the combined effect and treatment of ethanol-BUP intoxication. View Abstract—Gunnar Johanson

Microbial-derived aryl hydrocarbon receptor agonists/antagonists

The gut microbiome has an important role in modulating health, disease, and toxicity due in part to metabolites generated by diverse bacteria. Metabolites produced by gut microbes in turn modulate numerous regulatory pathways, due in part to modulation of soluble receptors present in the gut epithelium and tissues, once they are absorbed. The study by Cheng and colleagues is of interest because they characterize a class of metabolites derived from gut-derived 1,4-dihydroxy-2-naphthoic acid that can act as either agonists or antagonists of the aryl hydrocarbon receptor (AHR). Given the central role of the AHR in regulating xenobiotic and endobiotic metabolism, this study raises significant interest in how this class of compounds may contribute to the plethora of AHR-dependent changes mediated by this receptor ranging from target gene expression to other DNA binding-independent activities. Future studies could yield novel insight into how these and related metabolites modulate AHR-dependent toxicities and other AHR-dependent regulatory pathways. View Abstract—Jeffrey M. Peters