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.
| Original language | English |
|---|---|
| Pages (from-to) | 2763-2780 |
| Number of pages | 18 |
| Journal | Archives of Toxicology |
| Volume | 91 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2017 |
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Keywords
- DNA topoisomerase II
- Etoposide
- Infant leukaemia
- MLL fusion products
- Risk assessment
ASJC Scopus subject areas
- Toxicology
- Health, Toxicology and Mutagenesis
Cite this
Chemical exposure and infant leukaemia : development of an adverse outcome pathway (AOP) for aetiology and risk assessment research. / On behalf of the EFSA WG EPI1 and its other members.
In: Archives of Toxicology, Vol. 91, No. 8, 01.08.2017, p. 2763-2780.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Chemical exposure and infant leukaemia
T2 - development of an adverse outcome pathway (AOP) for aetiology and risk assessment research
AU - On behalf of the EFSA WG EPI1 and its other members
AU - Pelkonen, Olavi
AU - Terron, Andrea
AU - Hernandez, Antonio F.
AU - Menendez, Pablo
AU - Bennekou, Susanne Hougaard
AU - Angeli, Karine
AU - Fritsche, Ellen
AU - Leist, Marcel
AU - Mantovani, Alberto
AU - Price, Anna
AU - Viviani, Barbara
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - DNA topoisomerase II
KW - Etoposide
KW - Infant leukaemia
KW - MLL fusion products
KW - Risk assessment
UR - http://www.scopus.com/inward/record.url?scp=85019958919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019958919&partnerID=8YFLogxK
U2 - 10.1007/s00204-017-1986-x
DO - 10.1007/s00204-017-1986-x
M3 - Review article
AN - SCOPUS:85019958919
VL - 91
SP - 2763
EP - 2780
JO - Archiv fur Toxikologie
JF - Archiv fur Toxikologie
SN - 0003-9446
IS - 8
ER -