Effects of methyl methanesulfonate on mouse sperm chromatin structure and testicular cell kinetics

Evenson, Donald P.; Jost, Lorna K.; Baer, Rebecca K.

doi:10.1002/em.2850210208

Cited by 74 publications

(39 citation statements)

References 34 publications

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“…Several alkylating agents, including ethylnitrosourea, methyl methanesulphonate, thiotepa and triethylenemelamine, have been reported to result in sperm chromatin structural changes, as measured by flow cytometry (Evenson et al, 1985;Evenson et al, 1986;Evenson et al, 1989;Evenson et al, 1993). In the present study, the SCSA w /AO DNA denaturation assay revealed significant epididymal sperm nuclear structural effects of CPA exposure; maximal changes occurred in mid-spermiogenic elongating spermatids.…”

Section: Discussionsupporting

confidence: 48%

Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa

Codrington¹,

Hales²,

Robaire

2007

Human Reproduction

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BACKGROUND: The formation of mature sperm involves the expression of numerous proteins during spermiogenesis and the replacement of histones with protamines to package the genome. Exposure to cyclophosphamide (CPA), an anticancer alkylating agent, during spermiogenesis may disrupt chromatin condensation with adverse consequences to the offspring. METHODS: Adult male rats were given CPA in one of two schedules: (i) subchronic, 4 days-day 1 (100 mg kg 21) and days 2-4 (50 mg kg 21 per day) or (ii) chronic-daily (6.0 mg kg 21 per day). Animals were euthanized on days 14, 21 or 28. RESULTS: The effects of CPA on epididymal sperm chromatin structure were germ-cell-phase specific; mid-spermiogenic spermatids were most sensitive. The acridine orange DNA denaturation assay showed significant increases in susceptibility to denaturation (P < 0.01). Chromatin packaging assessment revealed 1,4-dithiothreitol-dependent chromomycin A3 DNA binding and less condensed, protaminedeficient sperm; the total thiol (P < 0.001) and protamine contents (P < 0.01), measured using monobromobimane and the HUP1N protamine 1 antibody, respectively, were reduced. The sperm basic proteome was also altered; proteins that were identified are involved in events during spermiogenesis and fertilization. CONCLUSIONS: Paternal exposure to CPA alters sperm chromatin structure, as well as the composition of sperm head basic proteins. We speculate that these changes underlie effects on fertilization and embryo development.

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Section: Discussionsupporting

confidence: 48%

Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa

Codrington¹,

Hales²,

Robaire

2007

Human Reproduction

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“…Sperm residing longer in the male reproductive tract can experience higher exposures to oxidative stress (49), but the implications for male infertility and heritable mutations are likely to be complex. Several studies have suggested that high levels of oxidative stress may render sperm incapable of fertilization, whereas others have suggested that sperm exposed to oxidative stress remain capable (49,50). Exposure to oxidative stress can induce DNA strand damage and breaks in both somatic and germ cells (49).…”

Section: Discussionmentioning

confidence: 99%

Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm

Wyrobek

Eskenazi

Young

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

369

206

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This study compares the relative effects of advancing male age on multiple genomic defects in human sperm [DNA fragmentation index (DFI), chromatin integrity, gene mutations, and numerical chromosomal abnormalities], characterizes the relationships among these defects and with semen quality, and estimates the incidence of susceptible individuals for a well characterized nonclinical nonsmoking group of 97 men (22-80 years). Adjusting for confounders, we found major associations between age and the frequencies of sperm with DFI and fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia (P < 0.01) with no evidence for age thresholds. However, we found no associations between age and the frequencies of sperm with immature chromatin, aneuploidies͞diploidies, FGFR2 mutations (Apert syndrome), or sex ratio in this cohort. There were also no consistent correlations among genomic and semen-quality endpoints, except between DFI and sperm motility (r ‫؍‬ ؊0.65, P < 0.001). These findings suggest there are multiple spermatogenic targets for genomically defective sperm with substantially variable susceptibilities to age. Our findings predict that as healthy males age, they have decreased pregnancy success with trends beginning in their early reproductive years, increased risk for producing offspring with achondroplasia mutations, and risk of fathering offspring with Apert syndrome that may vary across cohorts, but with no increased risk for fathering aneuploid offspring (Down, Klinefelter, Turner, triple X, and XYY syndromes) or triploid embryos. Our findings also suggest that the burden of genomic damage in sperm cannot be inferred from semen quality, and that a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects.DNA fragmentation ͉ human sperm ͉ achondroplasia ͉ sperm FISH ͉ Apert syndrome I t has become more socially acceptable to delay fatherhood, but the heritable consequences of this trend remain poorly understood. Since 1980, U.S. birth rates have increased up to 40% for men 35-49 years and have decreased up to 20% for men under 30 (1). Although it is well known that as women age, they are at increased risk for infertility, spontaneous abortion, and genetic and chromosomal defects among offspring, the association of male aging with these outcomes has been less well characterized (2).Advancing paternal age has been implicated in a broad range of abnormal reproductive and genetic outcomes (3, 4), including diminished semen quality (5), reduced fertility (6), increased frequencies of spontaneous abortions (7, 8), Ϸ20 autosomal dominant diseases including achondroplasia (ACH) and Apert syndrome (AS; see refs. 3 and 9), and several diseases of complex etiology such as schizophrenia (10). Among transmitted chromosomal defects, sex-chromosomal aneuploidy syndromes show substantial paternal contributions with some evidence of paternal-age effects (11-13).However, the mechanisms for age dependency of paternally transmitted genomic defects are ...

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“…Further research will indicate whether these different tests will detect other factors that may be significant for pregnancy outcome. Other studies on rodents that have used the same sperm samples known to have DNA strand breaks have confirmed a high level of DNA denaturation (Estop et al, 1993;Evenson et al, 1993b). Currently, the previous single COMP␣ t population has been replaced by percentage spermatozoa with non-detectable (formerly the main population) and detectable (moderate and high populations) DFI.…”

Section: Data Analysis-new Terminologymentioning

confidence: 98%

Sperm Chromatin Structure Assay: Its Clinical Use for Detecting Sperm DNA Fragmentation in Male Infertility and Comparisons With Other Techniques

Evenson

Larson

Jost

2002

Journal of Andrology

Self Cite

908

768

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The Sperm Chromatin Structure Assay (SCSA) was first described in the December 5, 1980 issue of Science (Evenson et al, 1980a). The data described in that article showed a significant difference between proven fertile and subfertility or infertility in men and bulls and the susceptibility to denaturation of their sperm nuclear DNA. A subsequent study (Evenson et al, 1984) described SCSA data obtained from men with testicular cancer. The data were heterogeneous, and begged the question, what was SCSA measuring? Great effort has been spent over the past 15 years on animal model systems, mostly related to dose-response toxicology experiments and large animal fertility trials. The results from these studies showed that SCSA was highly dose-responsive to toxicants, highly repeatable, and provided meaningful biological information on sperm nuclear DNA defects. The extensive data from nonhumans (Evenson et al, 1985(Evenson et al, , 1989a(Evenson et al, ,b, 1993a(Evenson et al, ,b,c, 1994Ballachey et al, 1987Ballachey et al, , 1988Evenson and Jost, 1993; Sailer et al, 1995a,b;Evenson, 1999a), and human toxicology and fertility studies (Evenson et al, 1978(Evenson et al, , 1980a(Evenson et al, ,b, 1984(Evenson et al, , 1991Evenson and Melamed, 1983;Evenson, 1999b;Larson et al, 1999Larson et al, , 2000Larson et al, , 2001 provide This work was supported in part by grant R827019 from the US Environmental Protection Agency, grants EPS-9720642 and OSR-9452894 from the National Science Foundation, and by SCSA Diagnostics, Inc. This is South Dakota Agricultural Experiment Station publication 3273 of the journal series.Correspondence to: Donald P. Evenson, Olson Biochemistry Laboratories, ASC 136, South Dakota State University, Brookings, SD 57006 (e-mail: donald evenson@sdstate.edu).Received for publication September 20, 2001; accepted for publication September 20, 2001. compelling evidence that SCSA will be useful in clinical human semen analysis (Figure 1).After reviewing current infertility center sites on the World Wide Web and approximately a dozen lay-oriented books on infertility and assisted reproductive technology (ART), it was amazing that not a single reference contained any information about the negative influence of fragmented sperm nuclear DNA on successful pregnancy outcome. Furthermore, few physicians are aware of scientific literature on this subject. Currently, if a spermatozoon has some motility as seen under a light microscope, and reasonable morphology, then many ART clinics assume that the sperm DNA must be fine. However, a number of cases have been documented in which couples have had multiple failed attempts at intracytoplasmic sperm injection (ICSI), even using donor eggs, and we found that the fragmentation of sperm DNA was above our threshold for less than 1% probability of achieving a successful pregnancy. Spermatozoa with defective DNA can fertilize an oocyte, produce high-quality early stage embryos, and then, in relationship to the extent of DNA damage, fail in producing a successful term ...

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Effects of methyl methanesulfonate on mouse sperm chromatin structure and testicular cell kinetics

Cited by 74 publications

References 34 publications

Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa

Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa

Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm

Sperm Chromatin Structure Assay: Its Clinical Use for Detecting Sperm DNA Fragmentation in Male Infertility and Comparisons With Other Techniques

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