Abstract
BackgroundSpermatozoal DNA damage is associated with poor sperm quality, disturbed embryonic development and early embryonic loss, and some genetic diseases originate from paternal de novo mutations. We previously reported poor repair of bulky DNA-lesions in rodent testicular cells.Methodology/Principal FindingsWe studied the fate of DNA lesions in the male germ line. B[a]PDE-N2-dG adducts were determined by liquid chromatography-tandem mass spectrometry, and de novo mutations were measured in the cII-transgene, in Big Blue®mice exposed to benzo[a]pyrene (B[a]P; 3×50 mg/kg bw, i.p.). Spermatozoa were harvested at various time-points following exposure, to study the consequences of exposure during the different stages of spermatogenesis. B[a]PDE-N2-dG adducts induced by exposure of spermatocytes or later stages of spermatogenesis persisted at high levels in the resulting spermatozoa. Spermatozoa originating from exposed spermatogonia did not contain DNA adducts; however de novo mutations had been induced (p = 0.029), specifically GC-TA transversions, characteristic of B[a]P mutagenesis. Moreover, a specific spectrum of spontaneous mutations was consistently observed in spermatozoa.Conclusions/SignificanceA temporal pattern of genotoxic consequences following exposure was identified, with an initial increase in DNA adduct levels in spermatozoa, believed to influence fertility, followed by induction of germ line de novo mutations with possible consequences for the offspring.
Highlights
Germ cells are unique, since they transmit their genetic information to the generation
The caput and cauda epididymal spermatozoa analysed at the various time points after exposure emanate from germ cells exposed at different stages of spermatogenesis; spermatogonial stem cells at
We considered the stem cell spermatogonia as the most important cell type to be studied with respect to mutation analysis since such mutations will be present in every spermatozoon generated from these progenitor cells, whereas mutations arising in the later stages of spermatogenesis are temporary and will affect only very few spermatozoa
Summary
Since they transmit their genetic information to the generation. Progenitor male germ cells carrying DNA damage have the potential to produce spermatozoa that, upon fertilization, may give rise to offspring with compromised health. Spermatozoa from infertile men exhibit higher levels of DNA damage compared to fertile men, and sperm DNA damage is strongly associated with low sperm quality [3,4,5,6,7,8] and reduced fertility [9], perturbed foetal development and early embryonic loss [10]. Spermatozoal DNA damage is associated with poor sperm quality, disturbed embryonic development and early embryonic loss, and some genetic diseases originate from paternal de novo mutations. We previously reported poor repair of bulky DNA-lesions in rodent testicular cells
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