For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells, including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant. We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells.
Bibliographical noteFunding Information:
The authors wish to thank Tom Phillips and Koki Azuma for preparation of the MitoQ bound nanoparticles, Mike Murphy for the generous gift of MitoQ, Dr. A. Kaidi for the gift of a commercially available antibody, Alexander Greenhough for help with western blots, Sharon Sanderson for help with image stream, Dr. Chris Arthur with the measurements of Benzene metabolites and Dr. Andrew Herman, Director of the University of Bristol Flow Cytometry Facility. The authors acknowledge the Edinburgh MRC Centre for Regenerative Medicine flow cytometry team, Fiona Rossi and Dr. Claire Dryer, for sorting services and for Perceptive Instruments for their help with the comet assay image. Funding for this study was generously provided by a grant from Children with Cancer and from support from the Tildy’s Trust. N.Z. received some salary support through research capability funding provided by the NIHR senior investigator award to Professor Tim Peters (reference NF-SI-0512-10026).