title: Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms.
abstract: Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events.
authors.affiliation: Department of Legal Medicine and Toxicology, University of Granada School of Medicine, Granada 18016, Spain. ajerez@ugr.es.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Hernández
authors.affiliation: Department of Biomedicine, Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona 08036, Spain. pmenendez@carrerasresearch.org.|Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain. pmenendez@carrerasresearch.org.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menéndez
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002648:Child; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*
chemical_list: D010575:Pesticides; D000110:Acetylcholinesterase; D004250:DNA Topoisomerases, Type II
keywords: DNA double-strand break; chromosomal rearrangements; hematopoietic stem/progenitor cells; infant and childhood leukemia; oxidative stress; pesticides; topoisomerase II