title: The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring.
abstract: The Organisation for Economic Co-operation and Development (OECD) has launched the Adverse Outcome Pathway (AOP) Programme to advance knowledge of pathways of toxicity and improve the use of mechanistic information in risk assessment. An AOP links a molecular initiating event (MIE) to an adverse outcome (AO) through intermediate key events (KE). Here, we present the scientific evidence in support of an AOP whereby chemicals that bind to tubulin cause microtubule depolymerization resulting in spindle disorganization followed by altered chromosome alignment and segregation and the generation of aneuploidy in female germ cells, ultimately leading to aneuploidy in the offspring. Aneuploidy, an abnormal number of chromosomes that is not an exact multiple of the haploid number, is a well-known cause of human disease and represents a major cause of infertility, pregnancy failure, and serious genetic disorders in the offspring. Among chemicals that induce aneuploidy in female germ cells, a large majority impairs microtubule dynamics and spindle function. Colchicine, a prototypical chemical that binds to tubulin and causes microtubule depolymerization, is used here to illustrate the AOP. This AOP is specific to female germ cells exposed during the periovulation period. Although the majority of the data come from rodent studies, the available evidence suggests that the MIE and KEs are conserved across species and would occur in human oocytes. The development of AOPs related to mutagenicity in germ cells is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.affiliation: Dipartimento Di Scienze Del Farmaco, Università Degli Studi Del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Massarotti
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: Division of Health Protection Technologies, Laboratory of Biosafety and Risk Assessment, ENEA CR Casaccia, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pacchierotti
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Russo
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001665:Binding Sites; D020090:Chromosome Segregation; D003078:Colchicine / Q000633:toxicity; D005260:Female; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009866:Oogenesis / Q000187:drug effects / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018570:Risk Assessment / Q000379:methods; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009153:Mutagens; D014404:Tubulin; D003078:Colchicine
keywords: chromosome missegregation; colchicine; female germ cells; meiotic spindle; microtubules; tubulin