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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
NASA NTRS1987

Melatonin in human preovulatory follicular fluid

Melatonin, the major hormone of the pineal gland, has antigonadotrophic activity in many mammals and may also be involved in human reproduction. Melatonin suppresses steroidogenesis by ovarian granulosa and luteal cells in vitro. To determine if melatonin is present in the human ovary, preovulatory follicular fluids (n = 32) from 15 women were assayed for melatonin by RIA after solvent extraction. The fluids were obtained by laparoscopy or sonographically controlled follicular puncture from infertile women undergoing in vitro fertilization and embryo transfer. All patients had received clomiphene citrate, human menopausal gonadotropin, and hCG to stimulate follicle formation. Blood samples were obtained by venipuncture 30 min or less after follicular aspiration. All of the follicular fluids contained melatonin, in concentrations (35.6 plus or minus 4.8 (plus or minus SEM) pg/mL) substantially higher than those in the corresponding serum (10.0 plus or minus 1.4 pg/mL). A positive correlation was found between follicular fluid and serum melatonin levels in each woman (r = 0.770; P less than 0.001). These observations indicate that preovulatory follicles contain substantial amounts of melatonin that may affect ovarian steroidogenesis.

Brzezinski, Amnon↗
NASA NTRS1997

Effects of Space Flight on Ovarian-Hypophyseal Function in Postpartum Rats

The effect of space flight in a National Aeronautics and Space Administration (NASA) shuttle was studied in pregnant rats. Rats were launched on day 9 of gestation and recovered on day 20 of gestation. On day 20 of gestation, rats were unilaterally hysterectomized and subsequently allowed to go to term and deliver vaginally. There was no effect of space flight on pituitary and ovary mass postpartum. In addition, space flight did not alter healthy and atretic ovarian antral follicle populations, fetal wastage in utero, plasma concentrations of progesterone and luteinizing hormone (LH) or pituitary content of follicle stimulating hormone (FSH). Space flight significantly increased plasma concentrations of FSH and decreased pituitary content of LH at the postpartum sampling time. Collectively, these data show that space flight, initiated during the postimplantation period of pregnancy, and concluded before parturition, is compatible with maintenance of pregnancy and has minimal effects on postpartum hypophyseal parameters; however, none of the ovarian parameters examined was altered by space flight.

Burden, H. W.↗
NASA NTRS2004

Hairlike Percutaneous Photochemical Sensors

Instrumentation systems based on hairlike fiber-optic photochemical sensors have been proposed as minimally invasive means of detecting biochemicals associated with cancer and other diseases. The fiber-optic sensors could be mass-produced as inexpensive, disposable components. The sensory tip of a fiber-optic sensor would be injected through the patient's skin into subcutaneous tissue. A biosensing material on the sensory tip would bind or otherwise react with the biochemical(s) of interest [the analyte(s)] to produce a change in optical properties that would be measured by use of an external photonic analyzer. After use, a fiber-optic sensor could be simply removed by plucking it out with tweezers. A fiber-optic sensor according to the proposal would be of the approximate size and shape of a human hair, and its sensory tip would resemble a follicle. Once inserted into a patient's subcutaneous tissue, the sensor would even more closely resemble a hair growing from a follicle (see Figure 1). The biosensing material on the sensory tip could consist of a chemical and/or cells cultured and modified for the purpose. The biosensing material would be contained within a membrane that would cover the tip. If the membrane were not permeable by an analyte, then it would be necessary to create pores in the membrane that would be large enough to allow analyte molecules to diffuse to the biosensing material, but not so large as to allow cells (if present as part of the biosensing material) to diffuse out. The end of the fiber-optic sensor opposite the sensory tip would be inserted in a fiberoptic socket in the photonic analyzer.

George, Thomas↗
NASA NTRS2017

Effects of Ionizing Radiation on Murine Gene Expression in Skin and Bone

Long duration spaceflight causes a negative calcium balance and reduces bone density in astronauts. The potential for exposure to space radiation to contribute to lasting decrements in bone mass is not yet understood. Sustained changes to bone mass have a relatively long latency for development, however skin is a radiation sensitive organ and changes in skin gene expression may serve as an early radiation biomarker of exposures and may correlate with adverse effects on skeletal tissue. Previous studies have shown that FGF18 gene expression levels of hair follicles collected from astronauts on the ISS rose over time. In the hair follicle, FGF18 signaling mediates radioresistance in the telogen by arresting the cell cycle, and FGF18 has the potential to function as a radioprotector. In bone, FGF18 appears to regulate cell proliferation and differentiation positively during osteogenesis and negatively during chondrogenesis. Cellular defense responses to radiation are shared by a variety of organs, hence in this study, we examined whether radiation induced gene expression changes in skin may be predictive of the responses of skeletal tissue to radiation exposure. We have examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR) after exposure to total body irradiation (TBI). To investigate the effects of irradiation on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated), and TBI (0.5 Gy Fe-56 600 MeV/n and 0.5 Gy H-1 150 MeV/n). Animals were euthanized one and 11 days post-IR. Statistical analysis was performed via a Student's ttest. In skin samples one day after IR, skin expression of FGF18 was significantly greater (3.8X) than sham-irradiated controls (3.8X), but did not differ 11 days post TBI. Expression levels of other radiation related genes (Nfe2l2, Trp53, Cdkn1a, FoxO3, Gadd45g, SOD1), was not different due to TBI at either time point. In bone (femora) TBI significantly increased (3.8X) expression of the pro-bone resorption cytokine, MCP-1, one day after TBI. FGF18 expression in skin and MCP- 1 expression in bone were found to be positively correlated (P less than 0.002, r=0.8779). Further, microcomputed tomography analysis of tibae from these animals showed reduced fractional cancellous bone volume (-21.7%) at 11 days post exposure. These results suggest that early radiation induced changes in FGF18 gene expression in skin may have value for predicting subsequent loss of cancellous bone mass.

space radiation↗
NASA NTRS2017

Ionizing Radiation Affects Gene Expression in Mouse Skin and Bone

Future long-duration space exploration beyond low earth orbit will increase human exposure to space radiation and microgravity conditions as well as associated risks to skeletal health. In animal studies, radiation exposure (greater than 1 Gy) is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Definitive measurements and detection of bone loss typically require large and specialized equipment which can make their application to long duration space missions logistically challenging. Towards the goal of developing non-invasive and less complicated monitoring methods to predict astronauts' health during spaceflight, we examined whether radiation induced gene expression changes in skin may be predictive of the responses of skeletal tissue to radiation exposure. We examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR) after exposure to total body irradiation (IR). To investigate the effects of irradiation on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated), and IR (0.5 Gy 56Fe 600 MeV/n and 0.5 Gy 1H 150 MeV/n), euthanized at one and 11 days post-irradiation (IR). To determine the extent of bone loss, tibiae were harvested and cancellous microarchitecture in the proximal tibia quantified ex vivo using microcomputed tomography (microCT). Statistical analysis was performed using Student's t-test. At one day post-IR, expression of FGF18 in skin was significantly greater (3.8X) than sham-irradiated controls, but did not differ at 11 days post IR. Expression levels of other genes associated with antioxidant response (Nfe2l2, FoxO3 and Sod1) and the cell cycle (Trp53, Cdkn1a, Gadd45g) did not significantly differ between the control and IR groups at either time point. Radiation exposure resulted in a 27.0% increase in FGF18-positive hair follicles at one day post-IR and returned to basal levels at 11 days post-IR. A similar trend was observed from FGF18 gene expression analysis of skin. In bone (femora), there was an increase in the expression of the pro-osteoclastogenic cytokine, MCP-1, one day after IR compared to non-irradiated controls. FGF18 expression in skin and MCP- 1 expression in bone were found to be positively correlated (P less than 0.002, r=0.8779). Further, microcomputed tomography analysis of tibia from these animals showed reduced cancellous bone volume (-9.9%) at 11 days post- IR. These results suggest that measurements of early radiation induced changes in FGF18 gene expression in skin may have value for predicting subsequent loss of cancellous bone mass. Further research may lead to the development of a relatively simple diagnostic tool for bone loss, with the advantage that hair follicles and skin are relatively easy to acquire from human subjects.

space radiation↗
NASA NTRS2016

Effects of Hindlimb Unloading and Ionizing Radiation on Murine Gene Expression in Skin and Bone

Long duration spaceflight causes a negative calcium balance and reduces bone density in astronauts. The underlying mechanisms of spaceflight-induced bone loss and the possible influences of both microgravity and radiation are not fully understood although emerging evidence suggests that these two factors may interact to result in increased bone loss. Previously, gene expression analysis of hair follicles from astronauts, as well as skin from space-flown mice, revealed changes in the expression of genes related to DNA damage and oxidative stress responses. These results resemble the responses of bone to spaceflight-like radiation and simulated weightlessness by hindlimb unloading (HU). Hence in this study, we initiated studies to determine whether skin can be used to predict the responses of bone to simulated microgravity and radiation. We examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR). To investigate the effects of irradiation andor HU on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated) (CT), hindlimb unloading (HU), 56Fe radiation (IR) and both HU+IR. Animals were euthanized 11 days post-IR, and results were analyzed by 1-way ANOVA. In skin samples, Cdkn1a was decreased to the same extent in HU and HU+IR (47 of CT). In addition, HU reduced FoxO3 expression (46 of CT) and IR increased Gadd45g expression 135 compared CT in skin. But in bone, HU increased FoxO3 expression 31 compared the level of CT. These results suggest that radiation and simulated weightlessness regulated simliar oxidative stress and cell cycle arrest genes in both skin and bone, although the time course and direction of changes may differ. This research may lead to the development of a relatively simple diagnostic tool for bone loss with the advantage that hair follicles and skin are relatively easy to acquire from subjects.

Terada, Masahiro↗
DOE OSTI2021

Transcription factor FOXC1 positively regulates SFRP1 expression in androgenetic alopecia

Androgenetic alopecia (AGA) is the most common type of hair loss dysfunction. Secreted frizzled related protein 1 (SFRP1) is found to be associated with hair loss, but its role in AGA and the regulation mechanism of its transcription level is unclear. The aim of our study is to explore the expression of SFRP1 in AGA samples and its transcriptional mechanism. Male frontal and occipital scalp hair follicles from AGA patients were collected, and human dermal papilla cells (DPCs) were isolated and cultured. SFRP1 gene was cloned and constructed into recombinant plasmids to perform dual-luciferase reporter assay. Transcription factor binding sites were predicted through the Jaspar website and further confirmed by the chromatin immunoprecipitation (ChIP) assay. Expression of genes in DPCs was determined by immunofluorescence (IF) staining, quantitative real-time PCR (qRT-PCR) and western blotting. Our findings showed that SFRP1 was highly expressed in DPCs of AGA patients. The core promoter region of SFRP1 was from −100 to +50 bp and was found to be positively regulated by forkhead box C1 (FOXC1), a transcription factor related to hair growth, both at mRNA and protein level in DPCs. Our study suggests that FOXC1 plays an important role in regulating SFRP1 transcription, which may provide new insights into the development of therapeutic strategies for the treatment of AGA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Transcriptional networks underlying a primary ovarian insufficiency disorder in alligators naturally exposed to EDCs

Interactions between the endocrine system and environmental contaminants are responsible for impairing reproductive development and function. Despite the taxonomic diversity of affected species and attendant complexity inherent to natural systems, the underlying signaling pathways and cellular consequences are mostly studied in lab models. To resolve the genetic and endocrine pathways that mediate affected ovarian function in organisms exposed to endocrine disrupting contaminants in their natural environments, we assessed broad-scale transcriptional and steroidogenic responses to exogenous gonadotropin stimulation in juvenile alligators (Alligator missippiensis) originating from a lake with well-documented pollution (Lake Apopka, FL) and a nearby reference site (Lake Woodruff, FL). Here, we found that individuals from Lake Apopka are characterized by hyperandrogenism and display hyper-sensitive transcriptional responses to gonadotropin stimulation when compared to individuals from Lake Woodruff. Site-specific transcriptomic divergence appears to be driven by wholly distinct subsets of transcriptional regulators, indicating alterations to fundamental genetic pathways governing ovarian function. Consistent with broad-scale transcriptional differences, ovaries of Lake Apopka alligators displayed impediments to folliculogenesis, with larger germinal beds and decreased numbers of late-stage follicles. After resolving the ovarian transcriptome into clusters of co-expressed genes, most site-associated modules were correlated to ovarian follicule phenotypes across individuals. However, expression of two site-specific clusters were independent of ovarian cellular architecture and are hypothesized to represent alterations to cell-autonomous transcriptional programs. Collectively, our findings provide high resolution mapping of transcriptional patterns to specific reproductive function and advance our mechanistic understanding regarding impaired reproductive health in an established model of environmental endocrine disruption.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Scale-dependent tipping points of bacterial colonization resistance

The commonly observed stability of natural microbiomes is important for their function, yet the ubiquity of microbiome stability remains enigmatic. The strongest form of stability, colonization resistance, protects residents against invaders and is often associated with specific porous structures, such as skin follicles or intestinal crypts. By systematically probing the colonization of fly gut–derived bacteria in microfluidic pores of varying sizes, we revealed that colonization patterns and invasion rates strongly depend on the pore size. Mathematical modeling shows that bacteria spontaneously tend to organize into a dense colonization-resistant state in pores exceeding a critical size. The scale dependence of stability and resilience could bias ecological filtering in microbiomes and should be considered in the design of microbial ecology experiments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Follistatin Forms a Stable Complex With Inhibin A That Does Not Interfere With Activin A Antagonism

Abstract Inhibins are transforming growth factor-β family heterodimers that suppress follicle-stimulating hormone (FSH) secretion by antagonizing activin class ligands. Inhibins share a common β chain with activin ligands. Follistatin is another activin antagonist, known to bind the common β chain of both activins and inhibins. In this study, we characterized the antagonist-antagonist complex of inhibin A and follistatin to determine if their interaction impacted activin A antagonism. We isolated the inhibin A:follistatin 288 complex, showing that it forms in a 1:1 stoichiometric ratio, different from previously reported homodimeric ligand:follistatin complexes, which bind in a 1:2 ratio. Small angle X-ray scattering coupled with modeling provided a low-resolution structure of inhibin A in complex with follistatin 288. Inhibin binds follistatin via the shared activin β chain, leaving the α chain free and flexible. The inhibin A:follistatin 288 complex was also shown to bind heparin with lower affinity than follistatin 288 alone or in complex with activin A. Characterizing the inhibin A:follistatin 288 complex in an activin-responsive luciferase assay and by surface plasmon resonance indicated that the inhibitor complex readily dissociated upon binding type II receptor activin receptor type IIb, allowing both antagonists to inhibit activin signaling. Additionally, injection of the complex in ovariectomized female mice did not alter inhibin A suppression of FSH. Taken together, this study shows that while follistatin binds to inhibin A with a substochiometric ratio relative to the activin homodimer, the complex can dissociate readily, allowing both proteins to effectively antagonize activin signaling.

Endocrinology & Metabolism↗
DOE OSTI2024

Histopathological characteristics of PRRS and expression profiles of viral receptors in the piglet immune system

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious viral disease that causes significant economic losses to the swine industry worldwide. PRRS virus (PRRSV) infection is a receptor-mediated endocytosis and replication process. The purpose of this study was to determine the localization and expression of four important PRRSV receptors in immunological organs of piglets. After piglets were infected with PRRSV, Hematoxylin and Eosin staining, immunofluorescence, and Western blot were used to perform histopathological examination and receptors distribution analysis. The results showed that PRRSV caused severe damage to the piglets’ immune organs, including atrophy of the thymus and swelling of lymph node. Histopathological lesions were mainly observed in the lung and lymph node and were characterized by interstitial pneumonia, collapsed follicles, exhaustion of germinal centers, and extensive hemorrhage. Immunofluorescence staining and Western blot results showed that the receptors of CD163 and NMHCII-A were mainly distributed in the thymus, hilar lymph nodes, and mesenteric lymph nodes. However, Sn and vimentin receptors were expressed at low levels in the immune organs of piglets. The distribution of the four receptors in the immune organs was more concentrated in the cortex but was more scattered in the medulla. Compared to the control group, the relative expression of the four receptors increased significantly in most immune organs after viral infection. In conclusion, our study examined the distribution and expression of four PRRSV receptors in immunological organs. We observed a significant increase in the expression of Sn, CD163, and vimentin following viral infection. These findings may provide potential targets for future antiviral reagent design or vaccine development.

Chen, Hong↗
NASA NTRS1980

Late degeneration in rabbit tissues after irradiation by heavy ions

Results are presented for investigations of the late effects of heavy-ion irradiation on rabbit tissues which were undertaken to assess the hazards associated with the long-term exposure of humans to heavy ions in space during such activities as the construction of solar power stations or voyages to Mars. White rabbits approximately six weeks old were exposed to various doses of collimated beams of 400-MeV/n Ne ions, 570 MeV/n Ar ions and Co-60 gamma rays directed through both eyes, and the responses of the various tissues (hair follicles, skin, cornea, lens, retina, Harderian glands, bone and forebrain) were examined. Proliferating tissues are found to exhibit high damage levels in the early and late periods following irradiation, while terminally differentiating tissues repond to radiation most intensely in the late period, years after irradiation, with no intermediate recovery. The results obtained from rabbits are used to predict the occurrence of late tissue degeneration in the central nervous system, terminally differentiating systems and stem cells of humans one or more decades following exposure to radiation levels anticipated during long-duration space flights. The studies also indicate that tissues may be prematurely aged in the sense that tissue life spans may be shortened without the development of malignancies.

Lett, J. T.↗
NASA NTRS1984

Effects of clinostat rotation on mouse meiotic maturation in vitro

The effects of microgravity on meiosis, fertilization, and early embryonic development in mammals are being examined by using a clinostat to reorient the cells with respect to the gravity vector. A clinostat capable of supporting mammalian cells in tissue culture has been developed. Initial studies have focused on examining the effects of clinostat rotation on meiotic maturation in mouse oocytes. Oocytes recovered from ovarian follicles were subjected to clinostat rotation on a horizontal or vertical axis or to static conditions for a 16 hr period. No gross morphological changes and no effects on germinal vesicle breakdown were observed under any rotation conditions (1/4, 1, 10, 30, 100 RPM). Success of meiotic progression to Metaphase II was comparable among experimental and control groups except at 100 RPM, where a slight inhibition was observed.

Wolgemuth, D. J.↗
NASA NTRS2004

Decreased Estrogen May Contribute to Osteopenia in Unloaded Bones

Progressive loss of weight-bearing bone in astronauts is one of the most serious impediments to long-duration spaceflight. Estrogen deficiency in women is an established factor in bone loss. Reduced sex hormone levels have been reported in male astronauts, but no data is available regarding spaceflight effects on female sex hormones. The objective of our study was to determine the role of estrogen in disuse osteopenia. The NASA developed hindlimb suspension (HLS) model was used to simulate the unloading disuse of weight-bearing bones experienced in space. Female Sprague-Dawley rats (age 77d; n = 20/group) were HLS or kept ambulatory (AMB) for 38 d and endocrine and bone indices determined. HLS of rats resulted in lower (p less than 0.01) bone mass (9%0), bone mineral content (BMC 13%) and mechanical strength (28%) compared to AMB animals. Plasma estradiol (E2) was lower (p = 0.03) in HLS (10.1 +/- 1.4 pg/ml) compared to AMB rats (16.7 +/- 2.6 pg/ml). E2 was positively correlated to BMC r(sup 2) = 0.67 and mechanical strength r(sup 2) = 0.61. These results suggest that reduced E2 plays a role in disuse osteopenia induced by HLS. Plasma or pituitary lutenizing hormone (LH) and follicle stimulating hormone (FSH) levels were not different in HLS versus AMB rats. However, pituitary LH was correlated to E2 (r(sup 2) = 0.57), suggesting changes in E2 were exerted at the level of the hypothalamus-pituitary axis. Understanding the role of estrogen in disuse osteopenia is necessary to the development of efficacious therapies for female astronauts, bed rest patients and the increasing number of individuals in our sedentary population suffering bone loss.

Tou, Janet↗
NASA NTRS2002

Cytoskeletal and functional changes in bioreactor assembled thyroid tissue organoids exposed to gamma radiation

Fischer rat thyroid cells were grown under low-shear stress in a bioreactor to a stage of organization composed of integrated follicles resembling small thyroid glands prior to exposure to 3 Gray-gamma radiation. Bioreactor tissues and controls (both irradiated and non-irradiated) were harvested at 24, 48, 96 and 144 hours post-exposure. Tissue samples were fixed and fluorescently labeled for actin and microtubules. Tissues were assessed for changes in cytoskeletal components induced by radiation and quantified by laser scanning cytometry. ELISA's were used to quantify transforming growth factor-beta and thyroxin released from cells to the culture supernatant. Tissue architecture was disrupted by exposure to radiation with the structural organization of actin and loss of follicular content the most obviously affected. With time post-irradiation the actin appeared disordered and the levels of fluorescence associated with filamentous-actin and microtubules cycled in the tissue analogs, but not in the flask-grown cultures. Active transforming growth factor-beta was higher in supernatants from the irradiated bioreactor tissue. Thyroxin release paralleled cell survival in the bioreactors and control cultures. Thus, the engineered tissue responses to radiation differed from those of conventional tissue culture making it a potentially better mimic of the in vivo situation.

Non-NASA Center↗
NASA NTRS2002

Response of thyroid follicular cells to gamma irradiation compared to proton irradiation: II. The role of connexin 32

The objective of this study was to determine whether connexin 32-type gap junctions contribute to the "contact effect" in follicular thyrocytes and whether the response is influenced by radiation quality. Our previous studies demonstrated that early-passage follicular cultures of Fischer rat thyroid cells express functional connexin 32 gap junctions, with later-passage cultures expressing a truncated nonfunctional form of the protein. This model allowed us to assess the role of connexin 32 in radiation responsiveness without relying solely on chemical manipulation of gap junctions. The survival curves generated after gamma irradiation revealed that early-passage follicular cultures had significantly lower values of alpha (0.04 Gy(-1)) than later-passage cultures (0.11 Gy(-1)) (P < 0.0001, n = 12). As an additional way to determine whether connexin 32 was contributing to the difference in survival, cultures were treated with heptanol, resulting in higher alpha values, with early-passage cultures (0.10 Gy(-1)) nearly equivalent to untreated late-passage cultures (0.11 Gy(-1)) (P > 0.1, n = 9). This strongly suggests that the presence of functional connexin 32-type gap junctions was contributing to radiation resistance in gamma-irradiated thyroid follicles. Survival curves from proton-irradiated cultures had alpha values that were not significantly different whether cells expressed functional connexin 32 (0.10 Gy(-1)), did not express connexin 32 (0.09 Gy(-1)), or were down-regulated (early-passage plus heptanol, 0.09 Gy(-1); late-passage plus heptanol, 0.12 Gy(-1)) (P > 0.1, n = 19). Thus, for proton irradiation, the presence of connexin 32-type gap junctional channels did not influence their radiosensitivity. Collectively, the data support the following conclusions. (1) The lower alpha values from the gamma-ray survival curves of the early-passage cultures suggest greater repair efficiency and/or enhanced resistance to radiation-induced damage, coincident with the expression of connexin 32-type gap junctions. (2) The increased sensitivity of FRTL-5 cells to proton irradiation was independent of their ability to communicate through connexin 32 gap junctions. (3) The fact that the beta components of the survival curves from both gamma rays and proton beams were similar (average 0.022 +/- 0.008 Gy(-2), P > 0.1, n = 39) suggests that at higher doses the loss of viability occurs at a relatively constant rate and is independent of radiation quality and the presence of functional gap junctions.

Non-NASA Center↗
NASA NTRS2002

Long-term (6-wk) hindlimb suspension inhibits spermatogenesis in adult male rats

The International Space Station will allow extended habitation in space and long-term exposure to microgravity (microG). A concern is the impact of long-term microG exposure on the ability of species to reproduce. The model often used to simulate microG is rat hindlimb suspension (HLS), where the hindlimbs are elevated above the cage floor with a tail harness. Experiments described here are the first to examine the effect of long-term HLS on testicular function in adult male rats. Free-roaming (controls), animals with only the tail harnessed but hindlimbs in contact with the cage floor (TO), and HLS animals were tested for 6 wk. Cryptorchidism was prevented in TO and HLS animals by partial constriction of the inguinal canal with sutures. All parameters were compared at the end of the 6-wk experiment. Testicular weights and spermatogenesis were significantly reduced by HLS, such that no spermatogenic cells beyond round spermatids were present and epididymides were devoid of mature sperm. In many tubules, loss of all germ cells, except a few spermatogonia, resulting in histopathology similar to the Sertoli cell, was observed. Spermatogenesis appeared unaffected in control and TO animals. Sertoli and Leydig cell appearance, testosterone, luteinizing hormone, and follicle-stimulating hormone levels, and epididymal and seminal vesicle weight were unchanged by HLS. Cortisone was not elevated by HLS; thus stress may not be a factor. These results demonstrate that spermatogenesis is severely inhibited by long-term HLS, whereas testicular androgen production is not. These results have significant implications regarding serious effects of long-term exposure to microG on the reproductive capability of scrotal mammals, including humans.

NASA Discipline Cell Biology↗
NASA NTRS2001

Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution

The RBE of protons has been assumed to be equivalent to that of photons. The objective of this study was to determine whether radiation-induced DNA and chromosome damage, apoptosis, cell killing and cell cycling in organized epithelial cells was influenced by radiation quality. Thyroid-stimulating hormone-dependent Fischer rat thyroid cells, established as follicles, were exposed to gamma rays or proton beams delivered acutely over a range of physical doses. Gamma-irradiated cells were able to repair DNA damage relatively rapidly so that by 1 h postirradiation they had approximately 20% fewer exposed 3' ends than their counterparts that had been irradiated with proton beams. The persistence of free ends of DNA in the samples irradiated with the proton beam implies that either more initial breaks or a quantitatively different type of damage had occurred. These results were further supported by an increased frequency of chromosomal damage as measured by the presence of micronuclei. Proton-beam irradiation induced micronuclei at a rate of 2.4% per gray, which at 12 Gy translated to 40% more micronuclei than in comparable gamma-irradiated cultures. The higher rate of micronucleus formation and the presence of larger micronuclei in proton-irradiated cells was further evidence that a qualitatively more severe class of damage had been induced than was induced by gamma rays. Differences in the type of damage produced were detected in the apoptosis assay, wherein a significant lag in the induction of apoptosis occurred after gamma irradiation that did not occur with protons. The more immediate expression of apoptotic cells in the cultures irradiated with the proton beam suggests that the damage inflicted was more severe. Alternatively, the cell cycle checkpoint mechanisms required for recovery from such damage might not have been invoked. Differences based on radiation quality were also evident in the alpha components of cell survival curves (0.05 Gy(-1) for gamma rays, 0.12 Gy(-1) for protons), which suggests that the higher level of survival of gamma-irradiated cells could be attributed to the persistence of nonlethally irradiated thyrocytes and/or the capacity to repair damage more effectively than cells exposed to equal physical doses of protons. The final assessment in this study was radiation-induced cell cycle phase redistribution. Gamma rays and protons produced a similar dose-dependent redistribution toward a predominantly G(2)-phase population. From our cumulative results, it seems likely that a majority of the proton-irradiated cells would not continue to divide. In conclusion, these findings suggest that there are quantitative and qualitative differences in the biological effects of proton beams and gamma rays. These differences could be due to structured energy deposition from the tracks of primary protons and the associated high-LET secondary particles produced in the targets. The results suggest that a simple dose-equivalent approach to dosimetry may be inadequate to compare the biological responses of cells to photons and protons.

NASA Discipline Radiation Health↗