RESUMEN
BACKGROUND: The past decade has seen numerous human health studies seeking to characterize the impacts of environmental exposures, such as organophosphate (OP) insecticides, on male reproduction. Despite an extensive literature on OP toxicology, many hormone-mediated effects on the testes are not well understood. OBJECTIVES: This study investigated environmental exposures to OPs and their association with the frequency of sperm chromosomal abnormalities (i.e., disomy) among adult men. METHODS: Men (n=159) from a study assessing the impact of environmental exposures on male reproductive health were included in this investigation. Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total disomy in sperm nuclei. Urine was analyzed using gas chromatography coupled with mass spectrometry for concentrations of dialkyl phosphate (DAP) metabolites of OPs [dimethylphosphate (DMP); dimethylthiophosphate (DMTP); dimethyldithiophosphate (DMDTP); diethylphosphate (DEP); diethylthiophosphate (DETP); and diethyldithiophosphate (DEDTP)]. Poisson regression was used to model the association between OP exposures and disomy measures. Incidence rate ratios (IRRs) were calculated for each disomy type by exposure quartiles for most metabolites, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. RESULTS: A significant positive trend was seen for increasing IRRs by exposure quartiles of DMTP, DMDTP, DEP and DETP in XX18, YY18, XY18 and total disomy. A significant inverse association was observed between DMP and total disomy. Findings for total sum of DAP metabolites concealed individual associations as those results differed from the patterns observed for each individual metabolite. Dose-response relationships appeared nonmonotonic, with most of the increase in disomy rates occurring between the second and third exposure quartiles and without additional increases between the third and fourth exposure quartiles. CONCLUSIONS: This is the first epidemiologic study of this size to examine the relationship between environmental OP exposures and human sperm disomy outcomes. Our findings suggest that increased disomy rates were associated with specific DAP metabolites, suggesting that the impacts of OPs on testis function need further characterization in epidemiologic studies.
Asunto(s)
Disruptores Endocrinos/orina , Exposición a Riesgos Ambientales/efectos adversos , Compuestos Organofosforados/orina , Aberraciones Cromosómicas Sexuales/inducido químicamente , Espermatozoides/efectos de los fármacos , Adulto , Disruptores Endocrinos/metabolismo , Exposición a Riesgos Ambientales/análisis , Cromatografía de Gases y Espectrometría de Masas , Humanos , Hibridación Fluorescente in Situ , Límite de Detección , Masculino , Persona de Mediana Edad , Compuestos Organofosforados/metabolismo , Distribución de Poisson , Aberraciones Cromosómicas Sexuales/estadística & datos numéricos , Espermatozoides/patología , Encuestas y Cuestionarios , Disomía Uniparental/inducido químicamente , Adulto JovenRESUMEN
BACKGROUND: The identification and characterization of cancer stem cells (CSCs) is imperative to understanding the mechanism of cancer pathogenesis. Growing evidence suggests that CSCs play critical roles in the development and progression of cancer. However, controversy exists as to whether CSCs arise from bone marrow-derived cells (BMDCs). METHODOLOGY AND PRINCIPAL FINDINGS: In the present study, n-nitrosodiethylamine (DEN) was used to induce tumor formation in female mice that received bone marrow from male mice. Tumor formation was induced in 20/26 mice, including 12 liver tumors, 6 lung tumors, 1 bladder tumor and 1 nasopharyngeal tumor. Through comparison of fluorescence in situ hybridization (FISH) results in corresponding areas from serial tumor sections stained with H&E, we determined that BMDCs were recruited to both tumor tissue and normal surrounding tissue at a very low frequency (0.2-1% in tumors and 0-0.3% in normal tissues). However, approximately 3-70% of cells in the tissues surrounding the tumor were BMDCs, and the percentage of BMDCs was highly associated with the inflammatory status of the tissue. In the present study, no evidence was found to support the existence of fusion cells formed form BMDCs and tissue-specific stem cells. CONCLUSIONS: In summary, our data suggest that although BMDCs may contribute to tumor progression, they are unlike to contribute to tumor initiation.
Asunto(s)
Células de la Médula Ósea/patología , Carcinógenos , Transformación Celular Neoplásica/patología , Neoplasias/inducido químicamente , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Cariotipo Anormal/inducido químicamente , Animales , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/fisiología , Dietilnitrosamina , Femenino , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias/epidemiología , Neoplasias/patología , Aberraciones Cromosómicas Sexuales/inducido químicamente , Cromosomas Sexuales/metabolismoRESUMEN
BACKGROUND: Chromosomal abnormalities contribute substantially to reproductive problems, but the role of environmental risk factors has received little attention. OBJECTIVES: We evaluated the association of polychlorinated biphenyl (PCB) and dichlorodiphenyldichloroethylene (p,p'-DDE) exposures with sperm sex-chromosome disomy. METHODS: We conducted a cross-sectional study of 192 men from subfertile couples. We used multiprobe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 to determine XX, YY, XY, and total sex-chromosome disomy in sperm nuclei. Serum was analyzed for concentrations of 57 PCB congeners and p,p'-DDE. Poisson regression models were used to calculate incidence rate ratios (IRRs) for disomy by exposure quartiles, controlling for demographic characteristics and semen parameters. RESULTS: The median percent disomy was 0.3 for XX and YY, 0.9 for XY, and 1.6 for total sex-chromosome disomy. We observed a significant trend of increasing IRRs for increasing quartiles of p,p'-DDE in XX, XY, and total sex-chromosome disomy, and a significant trend of increasing IRRs for increasing quartiles of PCBs for XY and total sex-chromosome disomy; however, there was a significant inverse association for XX disomy. CONCLUSIONS: Our findings suggest that exposure to p,p'-DDE may be associated with increased rates of XX, XY, and total sex-chromosome disomy, whereas exposure to PCBs may be associated with increased rates of YY, XY, and total sex-chromosome disomy. In addition, we observed an inverse association between increased exposure to PCBs and XX disomy. Further work is needed to confirm these findings.
Asunto(s)
Aneuploidia , Cromosomas Humanos Y/efectos de los fármacos , Diclorodifenil Dicloroetileno/toxicidad , Exposición a Riesgos Ambientales , Bifenilos Policlorados/toxicidad , Aberraciones Cromosómicas Sexuales/inducido químicamente , Adulto , Estudios Transversales , Diclorodifenil Dicloroetileno/sangre , Humanos , Hibridación Fluorescente in Situ , Masculino , Massachusetts , Distribución de Poisson , Bifenilos Policlorados/sangre , Análisis de Regresión , Espermatozoides/citología , Espermatozoides/efectos de los fármacosRESUMEN
BACKGROUND: Little is known about the effect of paternal nutrition on aneuploidy in sperm. We investigated the association of normal dietary and supplement intake of folate, zinc and antioxidants (vitamin C, vitamin E and beta-carotene) with the frequency of aneuploidy in human sperm. METHODS: Sperm samples from 89 healthy, non-smoking men from a non-clinical setting were analysed for aneuploidy using fluorescent in situ hybridization with probes for chromosomes X, Y and 21. Daily total intake (diet and supplements) for zinc, folate, vitamin C, vitamin E and beta-carotene was derived from a food frequency questionnaire. Potential confounders were obtained from a self-administered questionnaire. RESULTS: After adjusting for covariates, men with high folate intake (>75th percentile) had lower frequencies of sperm with disomies X, 21, sex nullisomy, and a lower aggregate measure of sperm aneuploidy (P Asunto(s)
Aneuploidia
, Antioxidantes/administración & dosificación
, Ácido Fólico/administración & dosificación
, Espermatozoides/citología
, Zinc/administración & dosificación
, Adulto
, Anciano
, Anciano de 80 o más Años
, Ácido Ascórbico/administración & dosificación
, Humanos
, Masculino
, Persona de Mediana Edad
, Estudios Retrospectivos
, Semen/efectos de los fármacos
, Aberraciones Cromosómicas Sexuales/inducido químicamente
, Vitamina E/administración & dosificación
, beta Caroteno/administración & dosificación
RESUMEN
Foi estudado o possível efeito mutagênico do epichlorohydrin (ECH) sobre as células germinativas de machos de Drosophila melanogaster. A alimentaçäo e a injeçäo de adultos com ECH näo foram capazes de induzir um aumento significativo na frequência de mutaçöes letais recessivas ligadas ao sexo em uma linhagem resistente a inseticida. A injeçäo dos adultos de uma linhagem sensível também näo teve efeito. Além do mais, resultados negativos foram obtidos quando ECH foi testato para a capacidade de induzir a perda do cromossomo do sexo e a näo-disjunçäo
Asunto(s)
Animales , Drosophila melanogaster , Insecticidas Organoclorados , Mutación , No Disyunción Genética , Células Germinativas , Resistencia a los Insecticidas , Aberraciones Cromosómicas Sexuales/inducido químicamenteRESUMEN
Nickel sulphate was injected into Drosophila melanogaster males at different concentrations in order to test the chemical for the induction of SLRL and SCL in germ cells. Nickel sulphate induced SLRL at concentrations tested, with the peak of activity at premeiotic and postmeiotic stages. It failed to produce SCL except at the highest concentration tested, where induction of XO males was significant for the pooled data.
Asunto(s)
Drosophila melanogaster/efectos de los fármacos , Níquel/farmacología , Animales , Deleción Cromosómica , Femenino , Genes Letales/efectos de los fármacos , Genes Recesivos/efectos de los fármacos , Masculino , Pruebas de Mutagenicidad , Aberraciones Cromosómicas Sexuales/inducido químicamenteRESUMEN
To extend the data on the mutagenic effects of intercalating agents in Drosophila melanogaster, chloroquine and quinacrine were tested for the induction of genetic damage in D. melanogaster males. Sex-linked recessive lethals and sex-chromosome loss induction were studied following treatment of adult males using a feeding technique. Our results show that both intercalating compounds increase significantly the frequency of sex-linked recessive lethals, but are unable to induce sex-chromosome loss in male germ cells under the conditions of testing.
Asunto(s)
Cloroquina/farmacología , Drosophila melanogaster/efectos de los fármacos , Quinacrina/farmacología , Animales , Cloroquina/toxicidad , Genes Letales , Genes Recesivos , Masculino , Pruebas de Mutagenicidad , Quinacrina/toxicidad , Aberraciones Cromosómicas Sexuales/inducido químicamenteRESUMEN
Tests for the induction of genetic damage in mammalian germ cells provide the data needed for human genetic risk assessment and are used as standards for judging the ability of shorter-term tests to predict genetic hazard. In this review, 15 mammalian germ-cell tests and their variants are described. These tests are of two general types: (a) those designed to detect certain classes of genetic damage (gene mutations, chromosome breakage and/or rearrangement, and chromosome mis-segregation), regardless of whether or not the endpoint scored has any significance to human health, and (b) those designed to detect phenotypes that have human health implications, while the nature of the genetic damage is not usually known. Exposure to a mutagenic agent presents no genetic hazard if the chemical or its metabolites fail to reach the reproductive cells. Tests for gonadal exposure are, therefore, important, as preliminaries or components of studies on germ-cell mutagenicity. Seven of these tests and their variants are briefly described in the second part of the paper.
Asunto(s)
Pruebas de Mutagenicidad/métodos , Anomalías Inducidas por Medicamentos/genética , Aneuploidia , Animales , Aberraciones Cromosómicas , Inversión Cromosómica , Reparación del ADN , Relación Dosis-Respuesta a Droga , Femenino , Genes Dominantes , Genes Letales , Genes Recesivos , Gónadas/efectos de los fármacos , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/genética , Masculino , Ratones , Mutágenos/farmacología , Mutación , No Disyunción Genética , Óvulo/efectos de los fármacos , Óvulo/ultraestructura , Aberraciones Cromosómicas Sexuales/inducido químicamente , Aberraciones Cromosómicas Sexuales/genética , Intercambio de Cromátides Hermanas/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/ultraestructura , Translocación Genética , Cigoto/ultraestructuraRESUMEN
The methylated oxypurine, 8-ethoxycaffeine (EOC), was tested for the induction of genetic damage in Drosophila melanogaster. Sex-linked recessive lethals, sex-chromosome loss and tanslocation induction were studied following treatment of adult males, using a feeding technique. Our results show that EOC induces sex-chromosome loss and translocations between the second and third chromosomes, but is unable to induce point mutations in male germ cells under our conditions of testing.
Asunto(s)
Cafeína/análogos & derivados , Mutación/efectos de los fármacos , Translocación Genética/efectos de los fármacos , Animales , Cafeína/toxicidad , Drosophila melanogaster/genética , Genes Letales , Masculino , Pruebas de Mutagenicidad , Aberraciones Cromosómicas Sexuales/inducido químicamenteRESUMEN
Drosophila melanogaster males carrying either a ring- or a rod-shaped X-chromosome were injected or fed with Trenimon (triaziquone) at concentrations ranging from 5 X 10(-5) to 2 X 10(-2) mM. The F1 generation was assayed for the occurrence of total sex chromosome loss and of Y-chromosome markers. Sex-linked recessive lethal tests were carried out simultaneously. The data show that significant induction of ring-X loss occurs already at very low treatment concentrations (5 X 10(-5) -10(-4) mM) whereas rod-X loss or Y-marker loss is only seen at 2-5 X 10(-3) mM and higher. Induction of sex-linked recessive lethals is observed from 10(-4) -10(-3) mM on. These results add to existing evidence that loss of ring-X chromosomes, induced by some chemicals, may proceed by a mechanism different from the kind of events leading to chromosome breakage, as measured by rod-X loss and Y-marker loss.
Asunto(s)
Cromosomas Sexuales/efectos de los fármacos , Triazicuona/toxicidad , Animales , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Femenino , Genes Letales , Masculino , Aberraciones Cromosómicas Sexuales/inducido químicamenteRESUMEN
Cytological investigations on the effects of sulphaguanidine on meiotic cells have been carried out. Concentrations of 4.165, 6.25 and 8.33 mg of the drug were orally administered to Swiss albino male mice as single and cumulative doses. In the latter the drug was fed consecutively for 5 days at 24 h intervals. Meiotic chromosomal preparations were made after 24 h and at weekly intervals up to the fifth week following drug administration. Structural aberrations like gaps, breaks, fragments and multivalent associations (translocations) were scored for assessing clastogenic activity. Mitoclasic effects were analysed by scoring the polyploids. A high rate of both autosomal and sex chromosomal univalents were recorded in the series treated. A non-clastogenic and a very weak mitoclasic property of the drug is suggestive and is comparable to observations on the effects of sulphadiazine previously reported.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Guanidinas/toxicidad , Meiosis/efectos de los fármacos , Sulfaguanidina/toxicidad , Administración Oral , Animales , Aberraciones Cromosómicas/inducido químicamente , Esquema de Medicación , Masculino , Ratones , Ratones Endogámicos , Aberraciones Cromosómicas Sexuales/inducido químicamente , Sulfaguanidina/administración & dosificaciónRESUMEN
Colcemid was fed to Drosophila melanogaster larvae throughout most of the larval period. Surviving individuals were then mated with untreated flies, and their progeny were examined for polyploid flies or flies resulting from X-chromosome nondisjunction. A total of 251 polyploid offspring was recovered from the experimental matings, none from the control. All of the polyploids were evidently triploids, and all but one were obtained from colcemid-fed females: males produced significantly lower frequencies of triploid offspring than females. The highest average frequency of triploid offspring obtained from any treatment group was 18%. Nonrandom distributions of triploid offspring were observed among females raised identically, indicating tht polyploidization occurs mitotically, rather than meiotically, giving rise to clones of tetraploid oogonia. 9 colcemid-fed females produced exclusively triploid offspring. Colcemid also caused a significant increase in X-chromosome nondisjunction in females, though the frequencies of such offspring were at least several-fold lower than the frequencies of triploid offspring. Somatic polyploidy was apparently also indiced since patches of large cells were found on the wings of some flies raised on colcemid-containing food. Various teratological abnormalities were observed among the treated flies, including deformed or missing eyes and partially duplicated thoraxes.
Asunto(s)
Aneuploidia , Demecolcina/farmacología , Drosophila melanogaster/efectos de los fármacos , Poliploidía , Teratógenos/farmacología , Anomalías Inducidas por Medicamentos/etiología , Animales , Femenino , Larva/efectos de los fármacos , Masculino , Mitosis/efectos de los fármacos , Aberraciones Cromosómicas Sexuales/inducido químicamente , Cromosoma X/efectos de los fármacosAsunto(s)
Danazol/efectos adversos , Trastornos del Desarrollo Sexual/inducido químicamente , Feto/efectos de los fármacos , Pregnadienos/efectos adversos , Aberraciones Cromosómicas Sexuales/inducido químicamente , Adulto , Trastornos del Desarrollo Sexual/genética , Trastornos del Desarrollo Sexual/cirugía , Femenino , Humanos , Lactante , Cariotipificación , Intercambio Materno-Fetal , Embarazo , Cromosoma XRESUMEN
Since trisomies produce adverse effects relatively late in development or even postnatally, they are an important component of the array of genetic damages that might be caused by environmental agents. Whole-chromosome aneuploidy (as opposed to breakage-derived aneuploidy) might come about secondarily from crossover depression, or could follow damage to the meiotic spindle or to kinetochores. For simplicity, the event-by whichever of the mechanisms-is referred to as meiotic nondisjunction (ND). A genetic method has been devised which is based on the facts that ND involving the sex chromosomes produces mostly viable mice, and that such exceptional animals can be externally recognized by the use of appropriate markers. The method is compared with the following other ND indicators: univalent and/or chiasma frequencies at M I; number of dyads at M II; extra sex chromosomes in spermatids; karyotypes in cleavage, morula, or blastocyst metaphases; and chromosome constitution of mid-gestation embryos. Some of the cytological endpoints are found to be unreliable. Various biological variables (germ-cell stage, sex, age) are examined with a view toward maximizing the chances for detecting induced nondisjunction. While experimental evidence on this question is equivocal, a consideration of the probable ND mechanisms suggests that the early spermatocyte (in stages including the premeiotic S phase) may be a favorable test object. The numerical sex-chromosome anomaly (NSA) method is useful not only in the study of ND but also in detecting breakage-derived chromosome losses induced in females, where the dominant lethal test is not easily applicable.
Asunto(s)
Aberraciones Cromosómicas , Técnicas Genéticas , Meiosis/efectos de los fármacos , Aberraciones Cromosómicas Sexuales/inducido químicamente , Animales , Intercambio Genético , Exposición a Riesgos Ambientales , Femenino , Masculino , Ratones , Mutágenos , Fenotipo , Aberraciones Cromosómicas Sexuales/genéticaRESUMEN
The negative influence of some insecticides on male fertility has been noted. We report our cytogenetic observations on a group of infertile insecticide workers. Increased chromosomal breakage was a constant finding and the Y chromosome was especially damaged. This may account for impaired spermatogenesis. Furthermore, the involvement of heterochromatic chromosomal variants both in the individual susceptibility to the chemically induced damage and in the reproductive fitness is emphasized.