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Detection of structural and numerical chomosomal abnormalities by ACM-FISH analysis in sperm of oligozoospermic infertility patients

Description: Modern reproductive technologies are enabling the treatment of infertile men with severe disturbances of spermatogenesis. The possibility of elevated frequencies of genetically and chromosomally defective sperm has become an issue of concern with the increased usage of intracytoplasmic sperm injection (ICSI), which can enable men with severely impaired sperm production to father children. Several papers have been published about aneuploidy in oligozoospermic patients, but relatively little is known about chromosome structural aberrations in the sperm of these patients. We examined sperm from infertile, oligozoospermic individuals for structural and numerical chromosomal abnormalities using a multicolor ACM FISH assay that utilizes DNA probes specific for three regions of chromosome 1 to detect human sperm that carry numerical chromosomal abnormalities plus two categories of structural aberrations: duplications and deletions of 1pter and 1cen, and chromosomal breaks within the 1cen-1q12 region. There was a significant increase in the average frequencies of sperm with duplications and deletions in the infertility patients compared with the healthy concurrent controls. There was also a significantly elevated level of breaks within the 1cen-1q12 region. There was no evidence for an increase in chromosome-1 disomy, or in diploidy. Our data reveal that oligozoospermia is associated with chromosomal structural abnormalities suggesting that, oligozoospermic men carry a higher burden of transmissible, chromosome damage. The findings raise the possibility of elevated levels of transmissible chromosomal defects following ICSI treatment.
Date: November 10, 2003
Creator: Schmid, T E; Brinkworth, M H; Hill, F; Sloter, E; Kamischke, A; Marchetti, F et al.
Partner: UNT Libraries Government Documents Department

DNA Repair Decline During Mouse Spermiogenesis Results in the Accumulation of Heritable DNA Damage

Description: The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-induced heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7-1 dbf). Analysis of chromosomal aberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm. Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.
Date: December 1, 2007
Creator: Marchetti, Francesco; Marchetti, Francesco & Wyrobek, Andrew J.
Partner: UNT Libraries Government Documents Department

"The Success of Captive Broodstock Programs Depends on High In-Culture Survival, ..." [from the Abstract], 2006-2007 Progress Report.

Description: The success of captive broodstock programs depends on high in-culture survival, appropriate development of the reproductive system, and the behavior and survival of cultured salmon after release, either as adults or juveniles. Continuing captive broodstock research designed to improve technology is being conducted to cover all major life history stages of Pacific salmon. Accomplishments detailed in this report are listed below by major objective. Objective 1: This study documented that captively reared Chinook exhibited spawn timing similar to their founder anadromous population. An analysis of spawn timing data of captively reared Chinook salmon that had received different levels of antibiotic treatment did not suggest that antibiotic treatments during the freshwater or seawater phase of the life cycle affects final maturation timing. No effect of rearing density was found with respect to spawn timing or other reproductive behaviors. Objective 2: This study investigated the critical period(s) for imprinting for sockeye salmon by exposing juvenile salmon to known odorants at key developmental stages. Molecular assessments of imprinting-induced changes in odorant receptor gene expression indicated that regulation of odorant expression differs between coho and sockeye salmon. While temporal patterns differ between these species, exposure to arginine elicited increases in odorant receptor mRNA expression in sockeye salmon. Objective 3: This study: (i) identified the critical period when maturation is initiated in male spring Chinook salmon and when body growth affects onset of puberty, (ii) described changes in the reproductive endocrine system during onset of puberty and throughout spermatogenesis in male spring Chinook salmon, (iii) found that the rate of oocyte development prior to vitellogenesis is related to body growth in female spring Chinook, and (iv) demonstrated that growth regimes which reduce early (age 2) male maturation slow the rate of primary and early secondary oocyte growth, but do not alter number of oocytes at ...
Date: April 8, 2009
Creator: Berejikian, Barry A.
Partner: UNT Libraries Government Documents Department

DNA repair decline during mouse spermiogenesis results in the accumulation of heritable DNA damage

Description: The post-meiotic phase of mouse spermatogenesis (spermiogenesis) is very sensitive to the genomic effects of environmental mutagens because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. We hypothesized that repeated exposures to mutagens during this repair-deficient phase result in the accumulation of heritable genomic damage in mouse sperm that leads to chromosomal aberrations in zygotes after fertilization. We used a combination of single or fractionated exposures to diepoxybutane (DEB), a component of tobacco smoke, to investigate how differential DNA repair efficiencies during the three weeks of spermiogenesis affected the accumulation of DEB-induced heritable damage in early spermatids (21-15 days before fertilization, dbf), late spermatids (14-8 dbf) and sperm (7- 1 dbf). Analysis of chromosomalaberrations in zygotic metaphases using PAINT/DAPI showed that late spermatids and sperm are unable to repair DEB-induced DNA damage as demonstrated by significant increases (P<0.001) in the frequencies of zygotes with chromosomal aberrations. Comparisons between single and fractionated exposures suggested that the DNA repair-deficient window during late spermiogenesis may be less than two weeks in the mouse and that during this repair-deficient window there is accumulation of DNA damage in sperm. Finally, the dose-response study in sperm indicated a linear response for both single and repeated exposures. These findings show that the differential DNA repair capacity of post-meioitic male germ cells has a major impact on the risk of paternally transmitted heritable damage and suggest that chronic exposures that may occur in the weeks prior to fertilization because of occupational or lifestyle factors (i.e, smoking) can lead to an accumulation of genetic damage in sperm and result in heritable chromosomal aberrations of paternal origin.
Date: February 21, 2008
Creator: Marchetti, Francesco; Marchetti, Francesco & Wryobek, Andrew J
Partner: UNT Libraries Government Documents Department

Chromosomal mosaicism in mouse two-cell embryos after paternal exposure to acrylamide

Description: Chromosomal mosaicism in human preimplantation embryos is a common cause ofspontaneous abortions, however, our knowledge of its etiology is limited. We used multicolor fluorescence in situ hybridization (FISH) painting to investigate whether paternally-transmitted chromosomal aberrations result in mosaicism in mouse 2-cell embryos. Paternal exposure to acrylamide, an important industrial chemical also found in tobacco smoke and generated during the cooking process of starchy foods, produced significant increases in chromosomally defective 2-cell embryos, however, the effects were transient primarily affecting the postmeiotic stages of spermatogenesis. Comparisons with our previous study of zygotes demonstrated similar frequencies of chromosomally abnormal zygotes and 2-cell embryos suggesting that there was no apparent selection against numerical or structural chromosomal aberrations. However, the majority of affected 2-cell embryos were mosaics showing different chromosomal abnormalities in the two blastomeric metaphases. Analyses of chromosomal aberrations in zygotes and 2-cell embryos showed a tendency for loss of acentric fragments during the first mitotic division ofembryogenesis, while both dicentrics and translocations apparently underwent propersegregation. These results suggest that embryonic development can proceed up to the end of the second cell cycle of development in the presence of abnormal paternal chromosomes and that even dicentrics can persist through cell division. The high incidence of chromosomally mosaic 2-cell embryos suggests that the first mitotic division of embryogenesis is prone to missegregation errors and that paternally-transmitted chromosomal abnromalities increase the risk of missegregation leading to embryonic mosaicism.
Date: October 14, 2008
Creator: Marchetti, Francesco; Bishop, Jack; Lowe, Xiu & Wyrobek, Andrew J
Partner: UNT Libraries Government Documents Department

DNA repair efficiency in germ cells and early mouse embryos and consequences for radiation-induced transgenerational genomic damage

Description: Exposure to ionizing radiation and other environmental agents can affect the genomic integrity of germ cells and induce adverse health effects in the progeny. Efficient DNA repair during gametogenesis and the early embryonic cycles after fertilization is critical for preventing transmission of DNA damage to the progeny and relies on maternal factors stored in the egg before fertilization. The ability of the maternal repair machinery to repair DNA damage in both parental genomes in the fertilizing egg is especially crucial for the fertilizing male genome that has not experienced a DNA repair-competent cellular environment for several weeks prior to fertilization. During the DNA repair-deficient period of spermatogenesis, DNA lesions may accumulate in sperm and be carried into the egg where, if not properly repaired, could result in the formation of heritable chromosomal aberrations or mutations and associated birth defects. Studies with female mice deficient in specific DNA repair genes have shown that: (i) cell cycle checkpoints are activated in the fertilized egg by DNA damage carried by the sperm; and (ii) the maternal genotype plays a major role in determining the efficiency of repairing genomic lesions in the fertilizing sperm and directly affect the risk for abnormal reproductive outcomes. There is also growing evidence that implicates DNA damage carried by the fertilizing gamete as a mediator of postfertilization processes that contribute to genomic instability in subsequent generations. Transgenerational genomic instability most likely involves epigenetic mechanisms or error-prone DNA repair processes in the early embryo. Maternal and embryonic DNA repair processes during the early phases of mammalian embryonic development can have far reaching consequences for the genomic integrity and health of subsequent generations.
Date: January 18, 2009
Creator: Marchetti, Francesco & Wyrobek, Andrew J.
Partner: UNT Libraries Government Documents Department

Spermatogonial stem cell renewal in the mouse as revealed by $sup 3$H- thymidine labeling and irradiation

Description: Procedures are described for sectioning and staining mouse testes, x- irradiation of mice, and classification of developing sperm cells. Tables are presented to show frequency of labeled cells following exposure to various doses of x radiation. A discussion is presented of types of spermatogonia surviving various radiation doses and times of incorporation of $sup 3$H-TdR in the cycle of the seminiferous epithelium. Models of stem cell renewal systems are described. (HLW)
Date: January 1, 1975
Creator: Oakberg, E.F. & Huckins, C.
Partner: UNT Libraries Government Documents Department

Molecular dosimetry of chemical mutagens: measurement of molecular dose and DNA repair germ cells

Description: Molecular dosimetry in the germ cells of male mice is reviewed with regard to in vivo alkylation of sperm heads, in vivo alkylation of sperm DNA, and possible alkylation of sperm protamine. DNA repair in male germ cells is reviewed with regard to basic design of experiments, DNA repair in various stages of spermatogenesis, effect of protamine on DNA repair following treatment with EMS or x radiation, and induction of DNA repair by methyl methanesulfonate, propyl methanesulfonate, and isopropyl methanesulfonate. (HLW)
Date: January 1, 1975
Creator: Sega, G.A.
Partner: UNT Libraries Government Documents Department

Effect of graded doses of ionizing radiation on the human testis. [X rays]

Description: Sixty-seven human subjects with normal testicular function were subjected to acute testicular irradiation in doses ranging from 8R to 600 R. Post irradiation observations included sperm counts and morphology, and radioimmunoassays for levels of reproductive steroids and hormones in urine (later plasma). Preliminary results and irradiation procedures are tabulated. An overview and analysis of results to date is published in a separate communication. (ERB)
Date: January 1, 1974
Creator: Rowley, M J; Leach, D R; Warner, G A & Heller, C G
Partner: UNT Libraries Government Documents Department