Vision of a near future: Bridging the human health-environment divide. Toward an integrated strategy to understand mechanisms across species for chemical safety assessment.

There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more comprehensive and reliable understanding of similarities and differences in biological pathways across a variety of species will better enable cross-species extrapolation of potential adverse toxicological effects. Ultimately, this would also advance the generation and use of mechanistic data for both human health and environmental RA. A workshop brought together representatives from industry, academia and government to discuss how to improve the use of existing data, and to generate new NAMs data to derive better mechanistic understanding between humans and environmentally-relevant species, ultimately resulting in holistic chemical safety decisions. Thanks to a thorough dialogue among all participants, key challenges, current gaps and research needs were identified, and potential solutions proposed. This discussion highlighted the common objective to progress toward more predictive, mechanistically based, data-driven and animal-free chemical safety assessments. Overall, the participants recognized that there is no single approach which would provide all the answers for bridging the gap between mechanism-based human health and environmental RA, but acknowledged we now have the incentive, tools and data availability to address this concept, maximizing the potential for improvements in both human health and environmental RA.

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids.

The redeployed drug combination of bezafibrate and medroxyprogesterone acetate (designated BaP) has potent in vivo anticancer activity in acute myelogenous leukemia (AML) and endemic Burkitt lymphoma (eBL) patients; however, its mechanism-of-action is unclear. Given that elevated fatty acid biosynthesis is a hallmark of many cancers and that these drugs can affect lipid metabolism, we hypothesized that BaP exerts anticancer effects by disrupting lipogenesis. We applied mass spectrometry-based lipidomics and gene and protein expression measurements of key lipogenic enzymes [acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl CoA desaturase 1 (SCD1)] to AML and eBL cell lines treated with BaP. BaP treatment decreased fatty acid and phospholipid biosynthesis from (13)C D-glucose. The proportion of phospholipid species with saturated and monounsaturated acyl chains was also decreased after treatment, whereas those with polyunsaturated chains increased. BaP decreased SCD1 protein levels in each cell line (0.46- to 0.62-fold; P < 0.023) and decreased FASN protein levels across all cell lines (0.87-fold decrease; P = 1.7 × 10(-4)). Changes to ACC1 protein levels were mostly insignificant. Supplementation with the SCD1 enzymatic product, oleate, rescued AML and e-BL cells from BaP cell killing and decreased levels of BaP-induced reactive oxygen species, whereas supplementation with the SCD1 substrate (and FASN product), palmitate, did not rescue cells. In conclusion, these data suggest that the critical anticancer actions of BaP are decreases in SCD1 levels and monounsaturated fatty acid synthesis. To our knowledge, this is the first time that clinically available antileukemic and antilymphoma drugs targeting SCD1 have been reported.

Metabolic responses produced by crude versus dispersed oil in Chinook salmon pre-smolts via NMR-based metabolomics.

Crude oil spills from tankers remain a serious threat along coastal California. Resource managers require information on the acute toxicity of treated and untreated oil, and their sublethal effects on wildlife. This investigation compared the toxic actions of the water-accommodated fraction (WAF) and the chemically-enhanced WAF (CEWAF; Corexit 9500) of Prudhoe Bay crude oil in pre-smolt Chinook salmon (Oncorhynchus tshawytscha) via nuclear magnetic resonance (NMR)-based metabolomics. Metabolite profiles from muscle samples, after 96h exposures, were measured using 1D (1)H NMR and compared via principal component analysis. It was determined that both WAF and CEWAF produced similar profiles in which amino acids, lactate and ATP comprised the highest intensity signals. Overall, metabolic substrates and growth measurements did not show residual effects of short-term exposure on long-term development. In conclusion, the 96h LC(50)s indicate dispersant application significantly decreased hydrocarbon potency and identified metabolites may be bio-indicators of hydrocarbon stress from hydrocarbon exposure.

Characterization of the metabolic actions of crude versus dispersed oil in salmon smolts via NMR-based metabolomics.

With maritime transport of crude oil from Alaska to California, there is significant potential for a catastrophic spill which could impact migrating salmon. Therefore, this study compared the lethal and sublethal metabolic actions of the water-accommodated fraction (WAF) and the chemically enhanced WAF (CEWAF, via Corexit 9500) of Prudhoe Bay crude oil in smolts of Chinook salmon (Onchorhyncus tshawytscha). After 96-h exposure to the CEWAF, the resulting LC50 was some 20 times higher (i.e., less toxic) than that of the WAF. Muscle and liver samples from surviving fish were collected and low-molecular weight metabolites were analyzed using one-dimensional (1)H and projections of two-dimensional (1)H J-resolved NMR. Principal component analysis (PCA), employed to analyze NMR spectra and identify most variance from the samples, revealed age-related metabolic changes in the fish within the replicated studies, but few consistent metabolic effects from the treatments. However, ANOVA results demonstrated that the dose-response metabolite patterns are both metabolite- and organ-dependent. In general, exposure to either WAF or CEWAF resulted in an increase of amino acids (i.e., valine, glutamine and glutamate) and a decrease of both organic osmolytes (i.e., glycerophosphorylcholine) and energetic substrates (i.e., succinate). The simultaneous increase of formate and decrease of glycerophosphorylcholine in the liver, or the decrease of glycerophosphorylcholine in muscle, may serve as sensitive sublethal biomarkers for WAF or CEWAF exposures, respectively. In conclusion, dispersant treatment significantly decreased the lethal potency of crude oil to salmon smolts, and the NMR-based metabolomics approach provided a sensitive means to characterize the sublethal metabolic actions.