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1.
Single sperm typing demonstrates that reduced recombination is associated with the production of aneuploid 24,XY human sperm 总被引:13,自引:0,他引:13
Shi Q Spriggs E Field LL Ko E Barclay L Martin RH 《American journal of medical genetics》2001,99(1):34-38
To account for the increased proportion of paternal nondisjunction in 47,XXY males as compared to other trisomies, it has been suggested that the XY bivalent, with its reduced region of homology, is particularly susceptible to nondisjunction. Molecular studies of liveborn Klinefelter syndrome (47,XXY) individuals have reported an association between the absence of recombination in the pseudoautosomal region and nondisjunction of the XY bivalent. In this study we examined single sperm from a normal 46,XY male to determine if there is any alteration in the recombination frequency of aneuploid disomic 24,XY sperm compared to unisomic sperm (23,X or Y). Two DNA markers STS/STS pseudogene and DXYS15 were typed in sperm from a heterozygous man to determine if recombination had occurred in the pseudoautosomal region. Individual unisomic sperm (23,X or Y) were isolated using a FACStar(Plus) flow cytometer into PCR tubes. To identify disomic 24,XY sperm, 3-colour FISH analysis was performed with probes for chromosomes X,Y and 1. The 24,XY cells were identified using fluorescence microscopy, each disomic sperm was scraped off the slide using a glass needle attached to a micromanipulator and then put into a PCR tube. Hemi-nested PCR analysis of the two markers was performed to determine the frequency of recombination. A total of 329 unisomic sperm and 150 disomic sperm have been typed. The frequency of recombination between the two DNA markers was 38.3% for the unisomic sperm, similar to frequencies previously reported. The 24,XY disomic sperm had an estimated recombination frequency of 25.3%, however, a highly significant decrease compared to the unisomic 23,X or 23,Y sperm (chi(2) = 10.7, P = 0.001). This direct analysis of human sperm indicates that lack of recombination in the pseudoautosomal region is a significant cause of XY nondisjunction and thus Klinefelter syndrome. Copyright Wiley-Liss. Inc. 相似文献
2.
Studies using gene-linkage analysis have suggested that abnormal recombination during meiosis may lead to the production of aneuploid gametes; however, there is little direct evidence of a link between the two in human males. We analysed spermatocytes in the pachytene stage from a man with extremely high aneuploidy rates in his sperm. Testicular tissue specimens of the infertile man and two vasectomy reversals were processed with immuofluorescent techniques to visualize synaptonemal complex and recombination foci and fluorescent in situ hybridization on spermatocytes and sperm with probes for chromosomes 13, 21, 18, X and Y. We observed no recombination between sex chromosomes in the infertile man, while in two controls, we observed recombination rates of 79.3 and 81.0% between the sex chromosomes. This was associated with a total sex aneuploidy rate of 41.61% in testicular sperm of the infertile man (0.44 and 0.62% in two controls). Recombination on chromosome 21 was reduced in the infertile man, with 10.62% of spermatocytes showing no recombination (0 and 1.67% in two controls), as well as chromosome 13, with 53.98% having < or =1 recombination foci (22.05 and 21.67% in two controls). This was associated with increased aneuploidy for those chromosomes. Chromosome 18 aneuploidy was slightly increased, although there was no apparent decrease in recombination. These results provide the first evidence of both recombination and non-disjunction abnormalities in the same individual. This is also the only reported case of an infertile man who shows no recombination between the sex chromosomes, despite the formation of the sex body. 相似文献
3.
Walmsley R Cohen J Ferrara-Congedo T Reing A Garrisi J 《Human reproduction (Oxford, England)》1998,13(Z4):61-70
This new procedure principally aims to avoid a second or possibly multiple surgical procedures for sperm extraction from the male partner in cases of limited amounts of sperm cells, where normal freeze-thaw protocols would fail. Patients (n = 34) diagnosed as azoospermic, extreme oligozoospermic, or oligoasthenozoospermic underwent the process of sperm cryopreservation within evacuated egg zonae. Other samples were allocated to conventional sperm freezing. Sperm samples were acquired using testicular sperm extraction (TESE), microepididymal sperm aspiration (MESA), or fresh ejaculate. Subsequently, five of these 34 couples have undergone in-vitro fertilization (IVF) and achieved normal fertilization using post-thawed spermatozoa frozen under zonae pellucidae in conjunction with intracytoplasmic sperm injection (ICSI). The average fertilization rate for the post-thaw injected spermatozoa was 65%. This is comparable with the regular fertilization rate of 65% for combined MESA and TESE using fresh spermatozoa. All patients underwent embryo transfer. The average implantation rate per embryo was 31%; nearly the same for regular MESA/TESE ICSI cycles (32%). The first pregnancy associated with this procedure concluded with the full term delivery of healthy twin girls on July 18, 1997. The remaining four thaw procedures resulted in another twin delivery, an ongoing singleton gestation, a negative pregnancy test and a biochemical pregnancy respectively. 相似文献
4.
Kuller JA Meyer WR Traynor KD Hartmann KE 《Human reproduction (Oxford, England)》2001,16(8):1553-1555
We wished to determine how clinicians manage sperm donors whose offspring have chromosomal or structural abnormalities. A directed, multiple-choice survey was given to reproductive endocrinologists and obstetrical geneticists to assess management of sperm donors whose offspring have chromosomal or structural abnormalities. The questionnaire was completed by 66 reproductive endocrinologists and obstetrical geneticists. Abnormalities and the most common inheritance modes included: Trisomy 21 (aneuploidy, maternal origin), Turner syndrome (aneuploidy, paternal origin), cleft lip/palate (multifactorial), VATER sequence (vertebral defects, imperforate anus, tracheo-esophageal fistula, radial and renal dysplasia, sporadic inheritance), and Hurler syndrome (autosomal recessive). Response choices were: (i) remove donor from programme, (ii) inform potential recipients of prior pregnancy outcomes and continue to use donor, or (iii) further study donor to assess karyotype/mutations. Inheritance mode appeared to influence decisions to remove donors from sperm banks; however, no clear consensus was noted. Guidelines exist for screening potential gamete donors, but not for managing donors whose offspring has a chromosomal or structural abnormality. Guidelines must be developed to manage sperm donors with untoward pregnancy outcomes. 相似文献
5.
Antinori S; Versaci C; Dani G; Antinori M; Pozza D; Selman HA 《Human reproduction (Oxford, England)》1997,12(2):286-291
Between July 1995 and May 1996, 36 patients with non-obstructive
azoospermia of secretory origin underwent intracytoplasmic injection of
spermatids. A previous histological biopsy was performed on all patients:
15 had spermatogenic arrest, a further 13 had Sertoli cell- only syndrome,
and the remaining eight had post-cryptorchidism tubal atrophy. The
ejaculate was duly examined and a complete absence of spermatozoa and
spermatids was confirmed, with only bacteria and debris being found.
Testicular sperm extraction (TESE) was then performed. In 19 out of 36
cases round spermatids only were found, while elongated spermatids were
found in the remaining 17. Both round and elongated spermatids were
isolated and used for injection. A total of 135 oocytes at metaphase II
were recovered from 19 partners and injected with round spermatids, while
123 mature oocytes from 17 partners were injected with elongated
spermatids. The number of oocytes fertilized, as judged by the presence of
two pronuclei, was 75 (55.5%) and 71 (57.7%) respectively. By 34 h after
injection, the number of embryos which had cleaved to the 2-cell stage was
56 (74.6%) with round spermatids and 55 (77.4%) with elongated spermatids.
All cleaved embryos were transferred into the uterus of the partners.
Clinical pregnancies were established in two cases of round spermatid
cycles (10.5%) (both are still ongoing), and three cases of elongated
spermatid cycles (17.6%) (two are still ongoing; one was lost after 8 weeks
of gestation). Chromosomal analysis showed that all fetuses had a normal
karyotype (three male and one female) with no chromosomal abnormalities.
相似文献
6.
Estrogen-related cancers are often associated with the hormone's tumor promoting activity. Recently, estradiol has also been demonstrated to induce gene mutations in the physiological concentration range. Mitotic disturbances are found at higher concentrations. In the present study we demonstrate data suggesting an additional mechanism for the induction of genetic damage, i.e. chromosomal breakage. Estrogen receptor-positive (BG-1) and -negative (UCI) human ovarian cancer cell lines were investigated for micronucleus formation after treatment with estradiol. BG-1 cells but not UCI cells showed an increase in micronucleus formation which correlated with the estradiol-induced cell proliferation. The specific estradiol receptor antagonist hydroxytamoxifen suppressed the formation of micronuclei in BG-1 cells. Increased micronucleus frequencies were also seen after normalization of the data to the number of cell divisions. Kinetochore analysis revealed a difference between micronuclei induced by picomolar concentrations of estradiol (kinetochore-negative) and micromolar concentrations (predominantly kinetochore-positive) leading to mitotic disturbances. In accordance with this finding, analysis of the cell cycle revealed decreased cell numbers in G(2)/M phase after treatment with picomolar concentrations, usually not found after mitotic disturbances. We hypothesize that hormone-specific forcing of responsive cells through the cell cycle leads to an override of checkpoints operating under homeostatic control of the cell cycle, resulting in genomic instability. 相似文献
7.
Vahid Zadmajid Mohammad Reza Imanpoor Ali Shabani Akbar Baharlouei 《Comparative clinical pathology》2013,22(4):703-711
The overall objective of the study was to investigate changes in quantitative parameters of goldfish (Carassius auratus) semen, testosterone (T), and gonadosomatic index (GSI) during the four seasons of the year (spring, summer, autumn, and winter). Simple environmental and hormonal treatments were used to induce out-of-season spawning in goldfish. The semen was taken from goldfish in different periods during the four seasons, and the characteristics of sperm and pH were analyzed. Plasma levels of T, GSI, and histological studies of the testes, as well as a range of indices of ovarian development, were measured. No significant differences were observed between volumes of semen which can be extracted per fish, in the four seasons (P?>?0.05). Significant differences were found between sperm motility at different seasons (P?<?0.05), as the maximum total duration of motility was observed in autumn (109.25?±?14.00 s). Sperm density showed a higher value during summer (57.30?±?10.41?spermatozoa (spz)?ml?1) and winter (65.09?±?80.40 spz ml?1) than values that were obtained from spring (48.00?±?7.08 spz ml?1) and autumn (40.42?±?16.54?×?109 spz ml?1) (P?<?0.05). However, spermatocrit (in percent) was higher in winter (39.90?±?4.74) compared with other seasons (P?<?0.05). Values of pH were higher in autumn (7.87?±?0.05) and in winter (7.83?±?0.03) than values that were obtained from other seasons. The peaks of T and GSI during spermiation in spring (T, 21.08 ng/ml, and GSI?=?5.21 %) and in summer (T, 23.32 ng/ml, and GSI?=?6.10 %), when most gonadal development took place, were statistically significantly higher than the levels observed during autumn (T, 15.08 ng/ml, and GSI?=?3.21 %) and winter (T, 22.18 ng/ml, and GSI?=?2.78 %) (P?<?0.05). Our results provided the statistically significant evidence of seasonal variation in sperm characteristics, T and GSI, for goldfish. These findings may be used to: (1) optimize semen collection for hatchery production and (2) characterize the potential impact of seasons on sperm quality and plasma androgen levels. 相似文献
8.
A L Rivas L Tintle E S Kimball J Scarlett F W Quimby 《Clinical immunology and immunopathology》1992,64(1):36-45
Familial Mediterranean Fever (FMF) is a human disorder characterized by recurrent fever of unknown origin (RFUO), renal amyloidosis, and evidence of peritonitis, pleuritis, and/or synovitis. This report suggests that Chinese Shar-pei (CSP) dogs suffer from a similar syndrome. CSP dogs with RFUO (n = 15) showed greater levels of IL-6 in serum than normal controls, hypergammaglobulinemia, and normal or supranormal in vitro lymphocyte blastogenesis in response to mitogen stimulation, when compared to healthy afebrile dogs. In patients 2 years old or older, RFUO was associated with renal failure, renal amyloidosis, and swollen joints. An epidemiological survey of privately owned dogs indicated a RFUO prevalence of 23% in CSP dogs (n = 132) and 1% in dogs of all breeds (n = 98). Increased levels of circulating cytokines, such as IL-6, have been shown to influence such processes as the febrile response, antibody production, and the synthesis of amyloid precursors. We propose that CSP dogs with RFUO, renal amyloidosis, and joint inflammation may serve as an animal model of FMF and that the clinical syndrome is associated with elevated levels of circulating IL-6. 相似文献
9.
Full-term pregnancies achieved with ICSI despite high levels of sperm chromatin damage 总被引:8,自引:0,他引:8
Gandini L Lombardo F Paoli D Caruso F Eleuteri P Leter G Ciriminna R Culasso F Dondero F Lenzi A Spanò M 《Human reproduction (Oxford, England)》2004,19(6):1409-1417
BACKGROUND: Sperm DNA integrity is essential for the accurate transmission of genetic information. The clinical significance of this assessment lies in its association with not only natural conception rates, but also the success of assisted reproduction technology (ART). It has been reported that sperm chromatin structure assay (SCSA) identified thresholds for negative pregnancy outcome after ART when the DNA fragmentation index (DFI), previously known as COMPalphat, was >30%. METHODS: In a prospective clinical study, we examined 34 male infertile patients, the husbands of women undergoing conventional IVF or ICSI. SCSA and ART were carried out on semen aliquots taken from the same ejaculate. Fertilization rate, embryo quality and pregnancy rates were correlated to SCSA parameters, DFI and highly DNA stainable (HDS) cells. RESULTS: No differences were seen in SCSA parameter values between patients initiating pregnancies and not doing so in either ICSI or conventional IVF. Pregnancies and normal delivery were obtained even with high levels of DFI. CONCLUSIONS: There is still controversy over whether analytical techniques currently in use are able to identify the level of damage to spermatozoa. Large-scale studies should be conducted in different clinical settings to determine the effects of sperm DNA damage on the outcome of ART. 相似文献
10.
11.
Wisanto A.; Magnus M.; Bonduelle M.; Liu J.; Camus M.; Tournaye H.; Liebaers I.; Steirteghem A.C.Van; Devroey P. 《Human reproduction (Oxford, England)》1995,10(10):2713-2718
An evaluation of the outcome of pregnancies resulting from intracytoplasmicsperm injection for severe male factor infertility was conductedby analysing the data obtained from the patients and/or theirobstetrician/gynaecologist on standardized questionnaires. Thedata from 424 pregnancies between April 1991 and September 1994were analysed. Early pregnancy loss before 16 weeks occurredin 99 cases (23.3%), including 48 clinical abortions (11.3%),47subclinical pregnancies (11.1%) and four ectopic pregnancies(0.9%). Vanishing twins and triplets, which could be regardedas early embryonic wastage, were found in 36 cases (8.5%). Onepregnancy was interrupted at week 15 of gestation because ofanhydramnios, and four pregnancies (0.9%) ended in spontaneouslate abortions before 26 weeks. A total of 320 pregnancies (75.5%)resulted in the birth of at least one child; 222 of these (69.3%)were singletons, 93 were twins (29.1%) and five were triplets(1.6%). The problems of prematurity and low birthweight wereespecially related to the multiplicity of pregnancies. Furthermore,from among the total of 423 babies born, we have observed threecases of stillbirth and five cases of neonatal mortality. Theperinatal mortality rate was therefore 18.9 per 1000 births.The results of this study show that the obstetric outcome ofthese pregnancies was similar to that obtained after conventionalin-vitro fertilization and other assisted reproduction techniques. 相似文献
12.
13.
Sanjeev Gumber Cynthia L. Courtney Karen R. Strait Prachi Sharma Julie E. Freebersyser Maria M. Crane 《Experimental and toxicologic pathology》2013,65(7-8):1121-1125
Retrograde ejaculation (RE) has been reported in humans and animals but RE with subsequent sperm calculi has rarely been reported. This report documents clinical and pathological findings of spontaneous sperm cystolithiasis in four rhesus macaques. While this condition has been associated with repeated electroejaculation, spontaneous sperm cystolithiasis is highly unusual. The animals presented with either stranguria, dysuria, hematuria, distended abdomen or lethargy. Ultrasound examination revealed several hyperechoic masses within the lumen of the urinary bladder. The animals were euthanized due to poor prognosis or study end points. Postmortem examination revealed multiple angular, amorphous, soft to firm, pale yellow to greenish-brown and variably sized calculi in the lumen of the urinary bladder or prostatic/penile urethra. Histologically, the calculi were composed of numerous sperm embedded in abundant brightly eosinophilic matrix. Based on gross and histologic findings, RE associated sperm cystolithiasis was diagnosed, with ulcerative urethritis as the major primary apparent etiology. To the authors’ knowledge, this is the first report of four spontaneous cases of sperm cystolithiasis in rhesus macaques. 相似文献
14.
Subbi Mathur H. Oliver Williamson Petrina V. Genco Philip F. Rust H. Hugh Fundenberg 《Journal of clinical immunology》1985,5(3):166-171
One hundred twenty-five fertile couples and 334 infertile couples were tested for the presence of cytotoxic and hemagglutinating antibodies to sperm. Elevated titers of sperm antibodies were absent in both partners of fertile couples. Of 79 infertile males with levels of sperm antibodies in the previously established negative range, 97% had wives who also had low titers of sperm antibodies. Of 255 infertile males positive for serum hemagglutinating antibodies, 56% had wives whose serum contained significant circulating hemagglutinating antibodies, while 93 of 202 (46%) males with significant cytotoxic antibody titers had wives whose serum contained elevated cytotoxic antibody titers. The females developed elevated titers of sperm antibodies in the serum and cervical mucus if their husbands had significant titers of hemagglutinating and cytotoxic sperm antibodies in the serum and seminal plasma samples. Females' isoimmunity to sperm was significantly associated with their husbands' autoimmunity to sperm and infertility. 相似文献
15.
Wennerholm U.-B.; Bergh C.; Hamberger L.; Nilsson L.; Reismer E.; Wennergren M.; Wikland M. 《Human reproduction (Oxford, England)》1996,11(5):1113-1119
The aim of this study was to describe the obstetric and perinataloutcome for births following intracytoplasmic sperm injection(ICSI). Of 210 infants born, 140 were singletons and 70 weretwins. There were no triplets or higher births. The multiplebirth frequency was 20%. Overall, 17% of deliveries were preterm,although for singleton pregnancies the incidence was reducedto 9%. The median birth weight of all live born infants was3168 g and of singletons 3470 g. Of all infants, 17% had a lowbirth weight (<2500 g) and 2% had a very low birth weight(<1500 g). Two major malformations occurred in two singletonchildren and four minor malformations occurred in four children.This was within the range of expected values in Sweden. Karyotypingwas performed in 58 pregnancies. All of them were normal. Theperinatal mortality was 0.5%. In conclusion, in this observationalstudy from Sweden of the first infants born after ICSI in ourprogramme, the incidence of multiple births, preterm births,low birth weight babies and congenital malformations was lowcompared with other series of in-vitro fertilization pregnanciesnot associated with ICSI. 相似文献
16.
Multiple pregnancies obtained by testicular spermatid injection in combination with intracytoplasmic sperm injection 总被引:18,自引:16,他引:2
Kahraman S; Polat G; Samli M; Sozen E; Ozgun OD; Dirican K; Ozbicer T 《Human reproduction (Oxford, England)》1998,13(1):104-110
Recent studies have shown that the injection of spermatid cells into the
human oocyte can result in normal fertilization, embryo development and
even delivery of live, healthy offspring. In our study, 23 azoospermic
cases with severe spermatogenetic defects in their testicular biopsy are
presented. The serum follicle stimulating hormone (FSH) concentrations and
histopathological results of these males have been documented and compared
in terms of fertilization and embryo development. The mean FSH value of the
azoospermic males was 15.8 +/- 2.3 mIU/l, ranging from 1.6 to 39 mIU/l.
Elongated spermatids were used in three cases only, as these more mature
forms were mostly present in the testicular sample. In the remaining 20
cases, only round spermatids were found for use in intracytoplasmic sperm
injection (ICSI). The fertilization rate with two pronuclei was 31.3%. The
fertilization rate was found to be as high as 71% in three patients in the
elongating and elongated spermatids group and as low as 25.6% in the round
spermatid group. A few immature, non-motile spermatozoa were seen in only
two cases from the elongated spermatid group. However, in the remaining
cases, no spermatozoa were observed. The number of pronuclear (PN) arrest
was quite high when only round spermatids were used (36.1%). Total
fertilization failure was observed in two cases from the round spermatid
group with Sertoli cell only and germ cell aplasia. A total of three
pregnancies was achieved in 23 cases (13.0%), two from the elongated
spermatid group and one from the round spermatid group. One biochemical
pregnancy with a round spermatid resulted in an early spontaneous abortion
and surprisingly, the remaining pregnancies were achieved with elongated
spermatids resulting in multiple pregnancies. One twin and one triplet
pregnancy were established following four embryo transfers in each patient.
The twin pregnancy resulted in a live birth with two healthy babies;
unfortunately, the triplet pregnancy ended in an abortion at 11 weeks. The
use of testicular spermatids in the treatment of non-obstructive
azoospermia may give hope by offering a novel treatment model. In cases
with very severe spermatogenetic defect, even multiple pregnancies can be
achieved with elongated spermatid cells by yielding a high implantation
rate. However, the efficiency of round spermatids in achieving
fertilization and pregnancy was disappointing.
相似文献
17.
Hanna Dar Ruth Merksamer Dolly Berdichevsky Miriam David 《American journal of medical genetics. Part A》1996,61(2):154-157
The study comprised 2,361 women, each with two consecutive normal uncomplicated pregnancies screened at 15–20 weeks gestation for maternal serum alpha-fetoprotein levels (AFP). In 1,816 of these women, maternal serum human chorionic gonadotropin (hCG) levels were tested as well. The proportion of women who had a second high AFP level (≥2.0 MOM) in their subsequent pregnancy was 6.5-fold higher as compared with the proportion of women who had normal levels of AFP in their first tested pregnancy. The relative chance of having a second positive result of a low level of AFP (AFP ≤0.5 MOM) in subsequent pregnancies was 3.8-fold higher. The relative chances of having a second positive result of high or low levels of hCG were 3.9- and 2.2-fold higher, respectively. It is concluded that there is a predisposition for abnormal levels of serum markers that is influenced by genetic and/or environmental factors. Therefore it is suggested that the individual's risk of having a Down syndrome baby, or other adverse pregnancy outcome that is derived from the serum markers' levels, should be adjusted taking into account unexplained high or low levels in previous pregnancies. A screening policy is suggested which is designed to yield a lower false-positive rate without affecting the detection rate of abnormal pregnancies. More data are needed before an accurate adjustment based on previous results can be made. © 1996 Wiley-Liss, Inc. 相似文献
18.
Transmission of Y chromosomal microdeletions from father to son through intracytoplasmic sperm injection 总被引:3,自引:0,他引:3
We conducted chromosomal analysis of three male infants fathered by severe oligozoospermic males with Y chromosomal microdeletions
through intracytoplasmic sperm injection (ICSI). Two of the infants had the same Y chromosomal microdeletions as their fathers.
The third infant also had a Y chromosomal microdeletion, which was longer than that found in his father. The results confirm
that Y chromosomal microdeletions are transmitted from a father to a son via ICSI and also suggest that the microdeletions
may be expanded during such transmission. Genetic counseling for infertile couples contemplating ICSI is important if the
male carries Y chromosomal microdeletions.
Received: January 11, 2002 / Accepted: May 19, 2002 相似文献
19.
Twenty-five mature rabbits were assigned in groups of five to be ejaculated at one of the following frequencies for a period of six weeks: Sexual rest (SR), one ejaculation on Friday (1 × F), four ejaculations on Friday (4 × F), one ejaculation daily Monday through Saturday (1 × M–S), and two ejaculations Monday, Wednesday, and Friday (2 × MWF). Upon slaughter after SR, the average distributions of sperm in the capita-corpora epididymides, caudae epididymides, and ductus deferentia were 184, 1,028, and 86 × 106, respectively. Ejaculation at each frequency significantly reduced the numbers of sperm found in the caudae epididymides, but neither weights of nor sperm numbers in the capitacorpora epididymides were affected by ejaculation frequency. While 79 ± 3% of extragonadal sperm were found in the caudae epididymides after SR, only 27 ± 5% were found there after 4 × F. This depletion of sperm represents 64% of those considered available for ejaculation. The data indicate that the ductus deferentia and ampullae of rabbits contain insufficient sperm to account for those normally found in a single ejaculum, and that the caudae epididymides are the immediate sources of most ejaculated sperm. The average calculated daily sperm production (82 × 106) was not affected by ejaculation frequency (P > 0.10). 相似文献
20.
Banerjee SK Young HW Barczak A Erle DJ Blackburn MR 《American journal of respiratory cell and molecular biology》2004,30(1):38-50
Adenosine signaling has been characterized in various physiologic systems, but little is known about the role of adenosine signaling in lung development. Alveogenesis and microvascular maturation are the final stages in lung development in mammals. Alveogenesis in the mouse begins on Postnatal Day 5, when the process of secondary septation plays a pivotal role in the expansion of the alveolar sacs and microvascular maturation. Adenosine deaminase null mice (ADA-/-) exhibit abnormalities in alveogenesis in association with elevated lung adenosine levels. Large-scale gene expression analysis of ADA-/- lungs using oligonucleotide-based microarrays revealed novel relationships between gene expression patterns and elevated lung adenosine during the stages of alveolar maturation. Genes regulating apoptosis, proliferation, and vascular development were shown to be altered, and decreased cell proliferation in association with increased alveolar type II cell apoptosis was shown to contribute to abnormal secondary septation in these mice. ADA enzyme therapy allowed for normal patterns of apoptosis, proliferation, and alveolar development in association with prevention of adenosine elevations. These findings were correlated with the presence of adenosine receptors in the developing lung, suggesting the involvement of receptor signaling. These studies provide evidence that elevated lung adenosine can lead to abnormal alveogenesis by disrupting patterns of cell proliferation and apoptosis. 相似文献