Genotoxicity of permethrin and clorpyriphos on human stem and progenitor cells at different ontogeny stages: implications in leukaemia development
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Abstract
The Mixed‐lineage leukemia (MLL) gene constitutes a genomic hotspot commonly rearranged/translocated in human acute leukemia (AL). MLL rearrangements (MLLr) represent a common hallmark of both de novo AL and therapy‐related acute myeloid leukemia (t‐AML). MLLr are the most common genomic alterations in infant B‐cell acute lymphoblasticleukemia (B‐ALL),which shows an unfavourable clinical outcome. Seminal studies revealedanin utero, pre‐natal, origin of these MLLr in pediatric B‐ALL. In addition, it has been suggested that chromosomal translocations involving the MLL gene are linked to a continuous/chronic exposure to genotoxic substances including topoisomerase II (TOP2) inhibitors (e.g. diet bioflavonoids) during pregnancy. Similarly, t‐AML in adults is largely the consequence of previous exposure to TOP2 inhibitors (mainly etoposide) used for the treatment of an earlier chemotherapy‐treated cancer.Pesticides and insecticides constitute a group of household products extensively used in our daily life. In 2017, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to investigate the plausible involvement of pesticide exposure as a risk factor for childhood leukaemia. This study conducted a literature‐based analysis aimed at investigating the potential link between leukemia development and exposure to different pesticides. Unfortunately, this study revealed a scarcity of robust experimental studies conducted to prospectively assess the cytotoxicity and genotoxicity of these compounds in infant‐adult leukemia development. Here, in collaboration with EFSA we analysedin vitro and in vivo the potential genotoxic contribution of Permethrin (PER) and Chlorpyrifos (CFP), two major active components present in pesticides and insecticides, in human hematopoietic stem and progenitor cells (HSPCs) at different ontogeny stages, spanning from embryonic to adult HSPCs, with a special emphasis in their abilityto induceMLL breaks/damage.This report summarizes the genotoxic effects of both PER and CFP inin vitroand in vivoassays.