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Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

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Abstract

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease—secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide—and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.

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Notes

  1. Even if MLL is not present in 100% of infant leukaemias, the ‘MLL-rearranged (MLL-r) infant leukaemia’, especially MLL-r B-ALL, is taken here as a model for the disease principally because of the quantity of scientific evidence.

Abbreviations

ALL:

Acute lymphoblastic leukaemia

HSPC:

Hematopoietic stem and progenitor cell

IATA:

Integrated Approach to Testing and Assessment

MLL:

Mixed-lineage or myeloid/lymphoid leukaemia (gene)

MLL-r:

Rearrangements of MLL gene

t-AL:

Therapy-associated acute leukaemia

topo II:

DNA topoisomerase II

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Acknowledgements

We thank Dr. Kenneth McCreath for critical reading and helping with English editing and.Marcella de Maglie for figure drawing. P.M is supported by the European Research Council (CoG-2014-646903), the Spanish Ministry of Economy-Competitiveness (SAF-SAF2013-43065), the Asociación Española Contra el Cáncer, the ISCIII/FEDER (PI14/01191-PI13/00168), the Obra Social La Caixa-Fundaciò Josep Carreras, the Inocente–Inocente Foundation and Generalitat de Catalunya. P.M is investigator of the Spanish Cell Therapy cooperative network (TERCEL). The EFSA Working Group EPI1 included also the following members: Karine Angeli, ANSES, France. Ellen Fritsche, IUF, Leibniz Research Institute for Environmental Medicine, Dusseldorf, Germany. Marcel Leist, University of Konstanz, Germany. Alberto Mantovani, Istituto Superiore di Sanità, Rome, Italy. Anna Price, EU JRC, Ispra, Italy. Barbara Viviani, University of Milan, Italy

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology and Clinical Research Unit, University of Oulu, Aapistie 5 B, POB5000, 90014, Oulu, Finland

    Olavi Pelkonen

  2. European Food Safety Authority (EFSA), Parma, Italy

    Andrea Terron

  3. University of Granada School of Medicine, Granada, Spain

    Antonio F. Hernandez

  4. Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain

    Pablo Menendez

  5. Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Pablo Menendez

  6. Centro de Investigación Biomédica en Red en Cancer del ISCIII (CIBERONC), Barcelona, Spain

    Pablo Menendez

  7. The Danish EPA, Copenhagen, Denmark

    Susanne Hougaard Bennekou

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  1. Olavi Pelkonen
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  2. Andrea Terron
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  3. Antonio F. Hernandez
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  4. Pablo Menendez
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  5. Susanne Hougaard Bennekou
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On behalf of the EFSA WG EPI1 and its other members

  • Karine Angeli
  • , Ellen Fritsche
  • , Marcel Leist
  • , Alberto Mantovani
  • , Anna Price
  •  & Barbara Viviani

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Correspondence to Olavi Pelkonen.

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Additional information

This article is based on the activity of the EFSA Working Group on Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson’s disease and childhood leukaemia. The Scientific Opinion is published in the EFSA Journal (Ockleford et al. 2017).

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Pelkonen, O., Terron, A., Hernandez, A.F. et al. Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research. Arch Toxicol 91, 2763–2780 (2017). https://doi.org/10.1007/s00204-017-1986-x

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  • DOI: https://doi.org/10.1007/s00204-017-1986-x

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