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Bionano Interactions: A Key to Mechanistic Understanding of Nanoparticle Toxicity
Published in Agnieszka Gajewicz, Tomasz Puzyn, Computational Nanotoxicology, 2019
David Power, Stefano Poggio, Hender Lopez, Vladimir Lobaskin
Predictive toxicology is now experiencing a transition from descriptive histopathological analyses to a data-rich science with a much greater focus on the understanding of biological mechanisms down to the molecular level. The mechanistic approach to toxicity assessment involves analysis of pathways based on particle tracking and on transcriptomics or metabolomics data, reflecting the activated system-level responses. In this paradigm, one assesses the possibility of initiating an adverse outcome pathway (AOP), which covers the evolution of a toxic process from its molecular initiating event (MIE) to downstream cascading key events (KEs), leading eventually to a pathology or adverse outcome. The pathways are recognized via biomarkers in specific bioassays developed to test each of these events.
Perception, Planning, and Scoping, Problem Formulation, and Hazard Identification
Published in Ted W. Simon, Environmental Risk Assessment, 2019
The scope of toxicity pathways to define the broader construct of adverse outcome pathway (AOP) as representing “existing knowledge concerning the linkage between the molecular initiating event (MIE) and an adverse outcome at the individual or population level.” By definition, an AOP spans multiple levels of biological organization. The MIE is defined as the initial point of chemical–biological interaction within an organism, and an AOP links a MIE to an adverse outcome.150–153
Advances in science and applications of air pollution monitoring: A case study on oil sands monitoring targeting ecosystem protection
Published in Journal of the Air & Waste Management Association, 2019
J.R. Brook, S.G. Cober, M. Freemark, T. Harner, S.M. Li, J. Liggio, P. Makar, B. Pauli
The adverse outcome pathway (AOP) is a conceptual framework for organizing existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance (Villeneuve et al. 2014). This resembles the exposome concept (Wild 2012) being explored to improve understanding of how environmental factors lead to chronic disease in humans (Rappaport and Smith 2010; Wild 2012). To be repeatable and adaptable to multiple types of ecosystems (or individuals), AOPs must be developed in accordance with a consistent set of core principles (Villeneuve et al. 2014).
Biological aspects of modern dental composites
Published in Biomaterial Investigations in Dentistry, 2023
Jan Tore Samuelsen, Jon E. Dahl
The ability to activate Nrf2 is an observed property in a range of sensitizers [67]. This knowledge has been used in the development of in vitro and chemical assays to test substances and materials for sensitizing potential [68]. The initial step in Nrf2 activation is modifications of cysteine thiols of the Keap1 protein, either by oxidation or by direct binding of electrophiles. The latter is the presumed mechanism of Nrf2 activation by sensitizers [69]. Assays that measure either Nrf2 activity in cultures cells or reactivity towards synthetic peptides containing cysteine are described in OECD protocols TG442c (keratinosense) [70] and TG442d (peptide-binding assay) [71], respectively. The replacement of animal tests by animal-free laboratory protocols is in line with the ‘3 R principle’ of animal testing (Refine, Reduce, and Replace) [72]. Following this principle, methods for the safety assessment of drugs and medical devices have increased. The recent revision of the ISO standard for evaluating the sensitizing potential of medical devices now includes a description of animal-free alternatives [55]. The understanding of the molecular and cellular mechanisms leading to adverse effects (adverse outcome pathways; AOPs) is essential in the development of such protocols. Both the Keratinosense assay (442c) and the peptide binding assay (442d) are reported to return good accuracy [73,74]. The previously reported spontaneous binding of several methacrylate monomers to GSH (a cysteine-containing tripeptide) may suggest an even easier and cheaper assay to measure sensitizing potential. By assuming that the thiol reactivity is the property of allergens that lead to sensitization (TG442C), the cell-based in vitro assays could potentially return false positives by compounds that oxidize Keap-1 thiols. Hence, cell-free systems, i.e. peptide binding assays, could be a better choice to avoid false positives, at least for screening purposes.
Using morphological, behavioral, and molecular biomarkers in Zebrafish to assess the toxicity of lead-contaminated sediments from a retired trapshooting range within an urban wetland
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Alex J Olson, Trevor Cyphers, Gretchen Gerrish, Colin Belby, Tisha C King-Heiden
Biomarkers of exposure are commonly used in both lab and field studies as a surrogate measure of biological impact. Decades of research have comprehensively characterized the inhibitory effects of Pb on the activity of ALA-D enzyme, which catalyzes the reaction of porphobilinogen (PBG) from δ-aminolevulinic acid (ALA) in the heme synthesis pathway. Inhibition of the ALA-D enzyme by Pb leads to decreased heme synthesis and produces an accumulation of ALA which subsequently induces the release of iron (Fe) from the iron transporter, ferritin (Oteiza et al. 1995). Ultimately, the reduction in ALA-D enzyme activity is thought to drive pathophysiology of Pb poisoning with respect to chronic hematological responses of Pb exposure. While blood Pb concentrations are a reliable index of Pb exposure, in terms of long-term monitoring its short half-life makes this infeasible. Despite inherent difficulties in determining the activity of the enzyme in practice Sakai (2000) and Lombardi, Peri, and Verrengia Guerrero (2010) for further discussion blood samples from exposed fish are typically used to assess ALA-D enzyme activity as a biochemical indicator of Pb exposure (Burden, Sandheinrich, and Caldwell 1998; Fernández, Martínez-Gómez, and Benedicto 2015; Kakkar and Jaffery 2005; Lombardi, Peri, and Verrengia Guerrero 2010; Schmitt et al. 2002, 2007; Van Der Oost, Beyer, and Vermeulen 2003). Given the small size of lab models such as zebrafish embryos/larvae, this methodology is problematic and an alternative molecular approach is more appropriate. Changes in gene expression typically occur more quickly than changes at the protein-level; therefore, a molecular biomarker for Pb exposure would be useful in that it enables detection of physiological changes in a “timely” manner – before toxicity is irreversible or at lower exposure concentrations (Hagger et al. (2006) and would likely be more sensitive in acute lab exposures or in caging/whole effluent testing as shown for metallothionein (Schmitt et al. 2007). These validated molecular biomarkers (molecular initiating events) may also be incorporated into Adverse Outcome Pathways (AOP), which are a powerful risk assessment tool (Ankley et al. 2009).