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    Mechanisms and consequences of DNA damage, response and apoptosis in spermatozoa.

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    J Laubenthal PhD thesis final submission Part 1.pdf (243.2Kb)
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    J Laubenthal PhD thesis final submission Part 2.pdf (6.623Mb)
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    Publication date
    2012-01-12
    Author
    Laubenthal, Julian
    Supervisor
    Anderson, Diana
    Gdula, Michal R.
    Keyword
    Spermatozoon
    Oxidative stress
    DNA-damage
    Fragile site FRA3B
    Fragile site FRA16D
    DNA-damage response
    Apoptosis
    Mother-father-newborn triad
    Lymphocyte
    Susceptibility
    Toxins
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    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Genetic and Reproductive Toxicology Laboratory, Division of Biomedical Sciences, School of Life Sciences.
    Awarded
    2011
    
    Metadata
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    Abstract
    DNA damage in spermatozoa is a crucial contributor to spontaneous abortion, severe genetic disease in the offspring and infertility. The chromatin of spermatozoa is highly compacted, transcriptionally and translationally silent, hence lacking DNA damage response (DDR). DDR foci follow within seconds after a DNA double strand break (DSB) and correlate to an abortive topoisomerase-IIb activity during spermiogenesis. When comparing the DSB frequencies at the two most fragile genomic loci (fragile sites FRA3B, FRA16D) in human and murine spermatozoa with lymphocytes, significantly increased DSB levels were detected in spermatozoa in both species. This corroborates that spermatozoa are more prone to DSBs than somatic cells. When comparing the DSB frequencies at FRA3B/FRA16D in spermatozoa of smokers with non-smokers, two-fold increases were found, probably caused by cigarette smoke components triggering abortive topoisomerase-II¿ activity. The phosphorylated DDR proteins H2AX and ATM were identified in human spermatozoa and murine spermatids using multicolour immunostaining with laser-scanning confocal microscopy (LSCM) and Western blots. Based on significantly increased DDR foci in spermatozoa of smoking men, but lacking DDR foci in response to in vitro challenge with H2O2, an abortive topoisomerase-IIb activity is the likely cause of DDR foci in spermatozoa. As DDR foci are susceptible to cigarette smoke, they can potentially be used as a novel biomarker. When comparing paternal spermatozoa, and lymphocytes as well as maternal and cord lymphocytes from 39 families for DSBs (via high-throughput LSCM pH2AX detection) and DNA fragmentation (Comet assay), significant increases were found in newborns of mothers exposed to environmental tobacco smoke and smoking fathers. When challenging lymphocytes and spermatozoa to different genotoxicants, significantly increased DNA damage in newborns compared to adults was found. This confirms an exceptional vulnerability in newborns, believed to cause increased susceptibly to disease in later life, including cancer.
    URI
    http://hdl.handle.net/10454/5332
    Type
    Thesis
    Qualification name
    PhD
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