Alterations In Germ Cells Research Articles

Utility of Dexrazoxane for the Attenuation of Epirubicin-Induced Genetic Alterations in Mouse Germ Cells

Dexrazoxane has been approved to treat anthracycline-induced cardiomyopathy and extravasation. However, the effect of dexrazoxane on epirubicin-induced genetic alterations in germ cells has not yet been reported. Thus, the aim of this study was to determine whether dexrazoxane modulates epirubicin-induced genetic damage in the germ cells of male mice. Our results show that dexrazoxane was not genotoxic at the tested doses. Furthermore, it protected mouse germ cells against epirubicin-induced genetic alterations as detected by the reduction in disomic and diploid sperm, spermatogonial chromosomal aberrations, and abnormal sperm heads. The attenuating effect of dexrazoxane was greater at higher dose, indicating a dose-dependent effect. Moreover, sperm motility and count were ameliorated by dexrazoxane pretreatment. Epirubicin induced marked biochemical changes characteristic of oxidative DNA damage including elevated 8-hydroxy-2ʹ-deoxyguanosine levels and reduction in reduced glutathione. Pretreatment of mice with dexrazoxane before epirubicin challenge restored these altered endpoints. We conclude that dexrazoxane may efficiently mitigate the epirubicin insult in male germ cells, and prevent the enhanced risk of abnormal reproductive outcomes and associated health risks. Thus, pretreating patients with dexrazoxane prior to epirubicin may efficiently preserve not only sperm quality but also prevent the transmission of genetic damage to future generations.

Assessment of heritable genetic effects using new genetic tools and sentinels in an era of personalized medicine

The challenge of estimating human health effects from damage to the germ line may be met in the genomic era. Understanding the genetic, as opposed to postconception developmental basis of birth defects is critical to their use in monitoring heritable genetic damage. The causes of common birth defects are analyzed here: mendelian genetic, multigenic, developmental, inherited, or combinational. Only a small fraction of these (noninherited, mendelian genetic) are likely to be informative relative to germ cell mutagenesis, and these won't be discernible against the general background of birth defects. Targeted genetic testing as part of personalized medicine could be integrated into a strategy for assessing germ cell alterations in populations. Thus, "sentinel mutations," as originally proposed by Mulvihill and Ceizel, need not be restricted to X-linked or dominant mutations or conditions visible at birth. Several new sentinels related to personalized medicine are proposed, based on health impact (likelihood of monitoring), frequency, and genetic target suitability (responsiveness to diverse mutational mechanisms). Candidates could include CYP genes (related to metabolism of xenobiotics) important in optimizing drug doses and avoiding adverse reactions. High frequency LDLR mutations (related to familial high cholesterol) predict myocardial infarction in approximately50% of individuals. The more common recessive genetic diseases (cystic fibrosis, phenylketonuria, and others) monitored in newborn screening programs could be informative given parental analysis. New opportunities for genetic analyses need to be coupled with epidemiological studies on environmental exposures. These could focus on adverse outcomes related to tobacco, the mostubiquitous and potent environmental mutagen.

Chapter 3 Caenorhabditis Nematodes as a Model for the Adaptive Evolution of Germ Cells

A number of major adaptations in animals have been mediated by alteration of germ cells and their immediate derivatives, the gametes. Here, several such cases are discussed, including examples from echinoderms, vertebrates, insects, and nematodes. A feature of germ cells that make their development (and hence evolution) distinct from the soma is the prominent role played by posttranscriptional controls of mRNA translation in the regulation of proliferation and differentiation. This presents a number of special challenges for investigation of the evolution of germline development. Caenorhabditis nematodes represent a particularly favorable system for addressing these challenges, both because of technical advantages and (most importantly) because of natural variation in mating system that is rooted in alterations of germline sex determination. Recent studies that employ comparative genetic methods in this rapidly maturing system are discussed, and likely areas for future progress are identified.

Alteration of lactate production and transport in the adult rat testis exposed in utero to flutamide

Although it is established that in utero exposure to the antiandrogen flutamide induces alteration of spermatogenesis in the adult rat testis offspring, the cellular and molecular mechanisms involved in such an effect remain to be investigated. In the present paper, by using as model adult rats exposed in utero to flutamide (0, 2, 10 mg/kg per day), we have investigated the hypothesis that germ cell alterations could be related to defects of energy metabolism and particularly to defects of the production and transport of lactate. Lactate is a preferential energy substrate produced by Sertoli cells and transported to germ cells by monocarboxylate transporters (MCT). A significant decrease (60%, P<0.001) in lactate production was observed in cultured Sertoli cells from rat testes exposed in utero to flutamide from the dose of 2 mg/kg per day. Such a decrease is concurrent to a decrease in lactate dehydrogenase A (LDHA) mRNA levels (evaluated through semiquantitative RT-PCR) and LDHA4 activity. The decrease in LDHA mRNA levels (to 64±9% of the control, P<0.05) was observed with the lowest dose (2 mg/kg per day) of flutamide tested. The decrease in LDHA mRNA levels was observed in both the whole testis and in isolated Sertoli cells, suggesting that such a decrease in LDHA expression occurred also in the (Sertoli) cells producing lactate. Lactate is transported from Sertoli cells to germ cells via MCT1 and MCT2. We immunolocalized MCT1 to all the different germ cell types and MCT2 exclusively to elongated spermatids. In the adult testis exposed in utero to flutamide, MCT1 (53±8%, P<0.02) and MCT2 (52±9%, P<0.02) mRNA levels were significantly reduced indicating that lactate transport to germ cells could be also altered. Together, these data support (i) the existence of a relationship between the antiandrogen activity and the energy metabolism in the testis and (ii) the concept of an androgen-dependent programming, occurring early in the fetal life in relation to the expression of some of the key genes involved in the production and transport of lactate in the seminiferous tubules.

Occupational exposure to genotoxic agents.

Millions of workers in the United States are potentially exposed each year to hazardous chemicals, dusts, or fibers in occupational settings. Some of these agents are genotoxic and may cause genetic alterations in the somatic or germ cells of exposed workers. Such alterations, if they occur in proto-oncogenes or tumor suppressor genes, which are involved in controlling cell growth or differentiation, may lead to the development of cancer. Genetic alterations in germ cells may also lead to reproductive failure or genetic disorders in subsequent generations. It has been estimated that occupational exposure accounts for 4% of all human cancers and up to 30% of cancer among blue-collar workers. Approximately 20,000 cancer deaths each year are attributable to occupational exposure in the United States. Occupational cancer and reproductive abnormalities have been listed on the National Occupational Research Agenda master list of research priorities as major occupational diseases and injuries.

Environmental effects of genotoxins (eco-genotoxicology).

Genotoxic chemicals can damage the genetic material of humans as well as that of organisms living in the environment. With respect to adverse effects, alterations induced in the germ line, leading to alterations in the genetic make-up of populations, are of primary concern in ecosystems, because somatic changes, even if they lead to a loss of individuals, will not be critical in populations with a large reproductive surplus. This is different in human toxicology where genetic alterations in germ cells as well as in somatic cells of any individual are of concern. Increased frequencies of mutations and related genetic alterations in the gene pools of individual species or populations in ecosystems have to be judged against the background of spontaneous mutations that have enabled species to survive and adapt in changing environments since the beginning of life on our planet, and which have played an important role as the substrate for evolutionary developments. Examples of the selection of altered phenotypes (and genotypes) in response to environmental pollution and environmental stress are melanism in moth populations, metal resistance in plants, insecticide resistance in insects and malaria resistance in humans. Pollution, in general, can represent a stress factor selectively leading to a change in genetic make-up. In addition, environmental genotoxins can directly alter gene pools. A change in the genetic constitution may be advantageous for certain populations living in stressful conditions, but may present a disadvantage for others, including man.(ABSTRACT TRUNCATED AT 250 WORDS)

Antispermatogenic effects of tolnidamine in langur ( [formula omitted

Tolnidamine (50 mg/kg body weight; twice a week; oral) was administered for 90 days to adult male langur monkeys ( Presbytis entellus entellus Dufresne) to assess its contraceptive potential. Semen weight, volume, seminal fluid volume, colour, pH and libido remained unchanged. Sperm motility, vitality and morphology were impaired with the advancement of treatment. Sperm density reduced to severe oligospermia following 75–90 days of treatment. Increased number of immature germ cells were also noticed. Resumption of changes to pretreatment range was observed following 90 days of cessation of treatment. However, sperm density remained low all through the recovery period of 150 days. Seminal fructose, ACP, LDH and citric acid concentrations did not change markedly. A significant depletion in GPC and magnesium levels was recorded during treatment and early recovery periods. Alterations in germ cells and Sertoli cells were also observed. A progressive but reversible rise in serum creatinine was evident. Other clinical parameters and body weight response revealed no drug-related alterations. In conclusion, tolnidamine medication induced irreversible inhibition of spermatogenesis.

Evolution postnatale de la teneur en zinc de l'épididyme et du testicule chez le rat dans les conditions normales et expérimentales

Postnatal testicular and epididymal zinc concentration in the rat was investigated by means of differential pulse polarography. The zinc concentration increased gradually from birth to day 90 in the testis and up to day 60-90 in the epididymis with an abrupt increase on day 21. No marked variation in the zinc content was observed all along the epididymal duct. Experimental castration and efferent duct ligation were carried out in order to assess the influence of blood-borne and luminal androgens on epididymal zinc content. In prepubertal rats, unilateral castration and efferent duct ligation did not affect the zinc content of the epididymis. Moreover, zinc concentration was not affected by bilateral castration which induced very low plasma testosterone levels. These results suggested that epididymal zinc content did not depend upon endocrine testicular secretions, especially androgens. On the other hand, in adult rats efferent duct ligation and cryptorchidism resulted in about 50 and 70% reduction, respectively of the testicular and epididymal zinc content. A correlation was found between the absence of testicular fluid and spermatozoa or the alteration of germ cells and the decrease in epididymal and testicular zinc content.