Development of the adverse outcome pathway “alkylation of <scp>DNA</scp> in male premeiotic germ cells leading to heritable mutations” using the <scp>OECD</scp>'s users' handbook supplement

Yauk, Carole L.; Lambert, Iain B.; Meek, M.E.; Douglas, George R.; Marchetti, Francesco

doi:10.1002/em.21954

Cited by 35 publications

(20 citation statements)

References 134 publications

(204 reference statements)

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“…There is increasing evidence for sub-linear dose responses for DNA reactive mutagens, such as ethyl methanesulfonate, and N -ethyl- N -nitrosourea in both somatic tissues and germ cells ( Bryce et al , 2010 ; Doak et al , 2007 ; Gocke and Muller, 2009 ; Lynch et al , 2011 ; O’Brien et al , 2015 ; Pottenger et al , 2009 ). This is indicative of a saturable repair response, where at lower doses the DNA damage is repaired, but repair processes are overwhelmed as doses increase ( Julien et al , 2009 ; Yauk et al , 2015b ). Because BaP induces mutations primarily through DNA adduct-forming metabolites, it is possible that the sub-linear dose response is attributable to a saturable repair mechanism for BaP adducts.…”

Section: Discussionmentioning

confidence: 99%

Benzo(a)pyrene Is Mutagenic in Mouse Spermatogonial Stem Cells and Dividing Spermatogonia

et al. 2016

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Although many environmental agents are established male germ cell mutagens, few are known to induce mutations in spermatogonial stem cells. Stem cell mutations are of great concern because they result in a permanent increase in the number of mutations carried in sperm. We investigated mutation induction during mouse spermatogenesis following exposure to benzo(a)pyrene (BaP). MutaMouse males were given 0, 12.5, 25, 50, or 100 mg/kg bw/day BaP for 28 days by oral gavage. Germ cells were collected from the cauda epididymis and seminiferous tubules 3 days after exposure and from cauda epididymis 42 and 70 days after exposure. This design enabled targeted investigation of effects on post-spermatogonia, dividing spermatogonia, and spermatogonial stem cells, respectively. BaP increased lacZ mutant frequency (MF) in cauda sperm after exposure of dividing spermatogonia (4.2-fold at highest dose, P < .01) and spermatogonial stem cells (2.1-fold at highest dose, P < .01). No significant increases in MF were detected in cauda sperm or seminiferous tubule cells collected 3 days post-exposure. Dose-response modelling suggested that the mutational response in male germ cells to BaP is sub-linear at low doses. Our results demonstrate that oral exposure to BaP causes spermatogonial stem cell mutations, that different phases of spermatogenesis exhibit varying sensitivities to BaP, with dividing spermatogonia representing a window of peak sensitivity, and that sampling spermatogenic cells from the seminiferous tubules at earlier time-points may underestimate germ cell mutagenicity. This information is critical to optimize the use of the international test guideline for transgenic rodent mutation assays for detecting germ cell mutagens.

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Section: Discussionmentioning

confidence: 99%

Benzo(a)pyrene Is Mutagenic in Mouse Spermatogonial Stem Cells and Dividing Spermatogonia

et al. 2016

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“…In addition, the term MOA, however, does not necessarily imply adversity [Meek et al, ]. An example of an application of the AOP concept for germ cell genomic damage is provided for DNA alkylation [Yauk et al, ]. The AOP concept is highly valuable when designing a new strategy as it provides structure and terminology for organizing toxicological understanding across different levels of biological organization.…”

Section: Approachmentioning

confidence: 99%

“…While creating the argument for what tests to conduct, greater weight should be given to consideration of endpoints of genomic damage associated with human disease, especially since human risk is being evaluated [MacGregor et al, ]. Furthermore, the genomic endpoint(s) should be consistent with those identified as key events in an AOP leading from the molecular initiating event to disease [Yauk et al, ; MacGregor et al, ]. A Quantitative Key Events/Dose‐Response Framework (Q‐KEDRF) provides a useful structured quantitative approach and guidance for a systematic examination of the dose response and timing of KEs resulting from a dose of a substance that potentially can induce genomic damage [Simon et al, ].…”

Section: Create Rational Biological Argumentmentioning

confidence: 99%

Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations

Dearfield

Gollapudi

Bemis

et al. 2016

Environ and Mol Mutagen

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For several decades, regulatory testing schemes for genetic damage have been standardized where the tests being utilized examined mutations and structural and numerical chromosomal damage. This has served the genetic toxicity community well when most of the substances being tested were amenable to such assays. The outcome from this testing is usually a dichotomous (yes/no) evaluation of test results, and in many instances, the information is only used to determine whether a substance has carcinogenic potential or not. Over the same time period, mechanisms and modes of action (MOAs) that elucidate a wider range of genomic damage involved in many adverse health outcomes have been recognized. In addition, a paradigm shift in applied genetic toxicology is moving the field toward a more quantitative dose-response analysis and point-of-departure (PoD) determination with a focus on risks to exposed humans. This is directing emphasis on genomic damage that is likely to induce changes associated with a variety of adverse health outcomes. This paradigm shift is moving the testing emphasis for genetic damage from a hazard identification only evaluation to a more comprehensive risk assessment approach that provides more insightful information for decision makers regarding the potential risk of genetic damage to exposed humans. To enable this broader context for examining genetic damage, a next generation testing strategy needs to take into account a broader, more flexible approach to testing, and ultimately modeling, of genomic damage as it relates to human exposure. This is consistent with the larger risk assessment context being used in regulatory decision making. As presented here, this flexible approach for examining genomic damage focuses on testing for relevant genomic effects that can be, as best as possible, associated with an adverse health effect. The most desired linkage for risk to humans would be changes in loci associated with human diseases, whether in somatic or germ cells. The outline of a flexible approach and associated considerations are presented in a series of nine steps, some of which can occur in parallel, which was developed through a collaborative effort by leading genetic toxicologists from academia, government, and industry through the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC). The ultimate goal is to provide quantitative data to model the potential risk levels of substances, which induce genomic damage contributing to human adverse health outcomes. Any good risk assessment begins with asking the appropriate risk management questions in a planning and scoping effort. This step sets up the problem to be addressed (e.g., broadly, does genomic damage need to be addressed, and if so, how to proceed). The next two steps assemble what is known about the problem by building a knowledge base about the substance of concern and developing a rational biological argument for why testing for genomic damage is ne...

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“…Once the weight of evidence (composed of biologic plausibility and empirical support) has been evaluated for each KER and the essentiality has been evaluated for each KE, the evidence in support of the overall AOP can be summarized, often in the form of a summary table as recommended by the OECD handbook (https://aopkb.org/ common/AOP_Handbook.pdf). The assessment of the AOP on "Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations" (https://aopkb.org/aopwiki/index.php/ Aop:15#Overall_Assessment_of_the_AOP) provides a good example of this type of summary (Yauk et al, 2015).…”

Section: Adverse Outcome Pathways-evolution Of the Conceptmentioning

confidence: 99%

Adverse Outcome Pathways--Organizing Toxicological Information to Improve Decision Making

Edwards

Tan

Villeneuve

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

172

126

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The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.

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Development of the adverse outcome pathway “alkylation of DNA in male premeiotic germ cells leading to heritable mutations” using the OECD's users' handbook supplement

Cited by 35 publications

References 134 publications

Benzo(a)pyrene Is Mutagenic in Mouse Spermatogonial Stem Cells and Dividing Spermatogonia

Benzo(a)pyrene Is Mutagenic in Mouse Spermatogonial Stem Cells and Dividing Spermatogonia

Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations

Adverse Outcome Pathways--Organizing Toxicological Information to Improve Decision Making

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