BOR - Papers in Press, published online ahead of print
October 4, 2002.
Biol Reprod 2002, 10.1095/biolreprod.102.007252
Biology of Reproduction 67, 1681-1687 (2002)
DOI: 10.1095/biolreprod.102.007252
© 2002 Society for the Study of Reproduction, Inc.
Models to Study Gravitational Biology of Mammalian Reproduction1
Janet Toua,
April Roncab,
Richard Grindelandb, and
Charles Wade2,b
a Lockheed Martin Sciences and Engineering
b Life Science Division, NASA Ames Research Center, Moffett Field, California 94035
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ABSTRACT
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Mammalian reproduction evolved within Earth's 1-g gravitational field. As we move closer to the reality of space habitation, there is growing scientific interest in how different gravitational states influence reproduction in mammals. Habitation of space and extended spaceflight missions require prolonged exposure to decreased gravity (hypogravity, i.e., weightlessness). Lift-off and re-entry of the spacecraft are associated with exposure to increased gravity (hypergravity). Existing data suggest that spaceflight is associated with a constellation of changes in reproductive physiology and function. However, limited spaceflight opportunities and confounding effects of various nongravitational factors associated with spaceflight (i.e., radiation, stress) have led to the development of ground-based models for studying the effects of altered gravity on biological systems. Human bed rest and rodent hindlimb unloading paradigms are used to study exposure to hypogravity. Centrifugation is used to study hypergravity. Here, we review the results of spaceflight and ground-based models of altered gravity on reproductive physiology. Studies utilizing ground-based models that simulate hyper- and hypogravity have produced reproductive results similar to those obtained from spaceflight and are contributing new information on biological responses across the gravity continuum, thereby confirming the appropriateness of these models for studying reproductive responses to altered gravity and the underlying mechanisms of these responses. Together, these unique tools are yielding new insights into the gravitational biology of reproduction in mammals.
environment, female reproductive tract, fertilization, male reproductive tract, pituitary hormones
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INTRODUCTION
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Mammalian reproduction evolved within Earth's 1-g gravitational field. Therefore, deviations from Earth's normal gravity, i.e., hypogravity (forces < 1 g) or hypergravity (forces >1 g), may compromise reproduction. Some interesting findings are emerging from spaceflight studies. For example, a transient but dramatic reduction in testosterone (T) has been reported during spaceflight in male rats and humans [1–4]. This observation suggests that fertility may be reduced during spaceflight, because adequate levels of T are required by adult males to maintain reproductive function. Pregnancy during spaceflight has been contraindicated, leading female astronauts to suppress their fertility cycles [5]. As a result, no systematic studies have been conducted to investigate the effect of deviations from 1 g on the reproductive physiology of nonpregnant mammals. Several studies have reported no detrimental effects on pregnancy, reproductive hormones, fetal development, parturition, or lactation in female rats following return to Earth [6–8].
In the era of the International Space Station with the eventual goal of space colonization, the emphasis of space biology research has begun to shift from investigations of acute responses to studies of chronic effects of altered gravity [9]. If space is to be successfully colonized, then a more comprehensive understanding of the effects of altered gravity on mammalian reproduction is needed. In addition, an understanding of the effects of altered gravity on reproductive physiology is imperative for the development of countermeasures. Here, we review the existing data on mammalian reproduction derived from spaceflight studies and from ground-based models of simulated hypo- and hypergravity. Such studies will provide the foundation to permit multiple generations of humans and other mammals to exist in space.
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GROUND-BASED MODELS IN GRAVITATIONAL BIOLOGY
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There are many challenges to overcome when conducting spaceflight experiments with mammals. For example, it is difficult to distinguish whether reproductive changes are due to gravity or other conditions aboard the spacecraft, such as increased radiation, noise, isolation, disrupted circadian rhythms, and stress [10]. Responses to decreased gravity on orbit versus increased gravity during landing are difficult to separate because subjects are not immediately recovered after flight. Thus, observed physiological changes may reflect recovery or landing (acute hypergravity) responses rather than in-flight (hypogravity) effects. Reproductive studies are also hampered by the short duration, high costs, and limited opportunities of spaceflight. To address some of these problems, scientists have designed simulation models of spaceflight.
One ground-based model for simulating hypogravity exposure in humans is bed rest with a 6° head-down tilt to initiate shifts in body fluids comparable to those experienced during orbital spaceflight. Bed rest is a convenient method that is reasonably effective at reproducing the major symptoms of hypogravity experienced during spaceflight [11]. In rodent studies, the Morey-Holton hindlimb suspension (HLS) model has been used to simulate the major physiological effects of hypogravity. The HLS model involves suspending rats by the tail base to produce a 30° head-down position that complements the human 6° head-down tilt utilized in bed-rest studies [11, 12].
A ground-based model for studying hypergravity is centrifugation. With the use of proper controls for Coriolis effects, centrifugation allows for an infinite number of graded increases in gravitational load and is therefore applicable to a broad range of gravity-related questions. Acute centrifugation is used to mimic the hypergravity associated with launch and landing, whereas chronic centrifugation is used to study the long-term effects of increased gravity on biological systems.
Ground-based models have been used successfully in studies of the musculoskeletal system, to validate spaceflight experiments, and to define adaptation to the space environment [13]. Advantages of using ground-based models are the ability to control environmental factors more effectively than can often be achieved in spaceflight studies. Animals adapt well to ground-based models, thereby minimizing stress-associated physiological effects [14–16]. Therefore, ground-based models are potentially valuable tools for investigating reproduction during exposure to hyper- and hypogravity.
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EFFECTS OF SPACEFLIGHT ON MALE REPRODUCTION
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The testes are important organs of the male reproductive system with the dual function of spermatogenesis and steroidogenesis. Testosterone (T), the principal androgen, maintains reproductive organ function and stimulates sperm production in adult males. In most spaceflight studies, reduced testes weight and T levels were reported (Table 1) [2–4, 17]. Reduction in T following spaceflight is not always accompanied by reduced spermatogenesis [4]. Reduction in T levels may not be great enough or the duration may not be long enough to affect spermatogenesis. Systematic examination of androgen-dependent accessory sex glands may provide valuable insight. However, to our knowledge no researchers have systematically examined the effects of spaceflight on the accessory sex glands. In one published study, no effects on T were reported [18]. Inconsistent results may occur because T levels in the blood fluctuate across the circadian cycle. Ortiz et al. [19], avoiding the bias inherent in single measurement studies by collecting 24-h urinary T data, reported increased postflight urinary T in rats followed by a return to normal T levels. This finding contrasts with those of other reports of reduced T in response to spaceflight [2–4, 17]. The use of urine samples may provide a more comprehensive analysis of effects on the hypothalamic-pituitary-gonadal (HPG) axis. Clearly, more studies are required before definitive statements can be made regarding effects of spaceflight on male reproductive hormones.
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TABLE 1. Summary of the effects of spaceflight, suspension models of simulated hypogravity, and centrifugation models of hypergravity on male reproductive physiology
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Reproductive changes do not always occur at the testes but may occur at the level of the hypothalamus or pituitary. The hypothalamus produces GnRH, which acts on the pituitary gland to stimulate secretion of FSH and LH. Decreased T in various biological fluids of male astronauts occurred in parallel with increased plasma LH, which returned to normal after flight [20]. The in-flight increase in LH was suggested to be a compensatory mechanism in response to decreased T levels. However, Ortiz et al. [19] reported increased urinary LH in rats in response to increased urinary T after flight. In both animals and humans, the pituitary responded to changes in plasma T, indicating that the HPG axis was not impaired by spaceflight. Reproductive changes in males following spaceflight suggest that hypogravity or other factors associated with spaceflight may compromise male reproduction.
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EFFECTS OF SIMULATED HYPOGRAVITY ON MALE REPRODUCTION
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Ground-based models used to simulate hypogravity have facilitated the interpretation of spaceflight studies. In ground-based simulation models, stress effects can be controlled, which has important implications for research on reproduction because stress responses are known to adversely affect reproductive function. For example, in animals and humans increased cortisol excretion associated with stress can result in reduced serum T levels [21–24]. Thus, it has been difficult to ascertain whether the reproductive changes are due to stress or to hypogravity associated with spaceflight. Chronic stress in spaceflight rats was indicated by higher adrenal gland weights compared with controls [25]. In studies of astronauts aboard the MIR Space Station, increased cortisol was reported during spaceflight [26]. In ground-based studies utilizing bed rest to simulate hypogravity, Blanc et al. [27] found elevated cortisol excretion during the initial 4 wk of bed rest. Vernikos et al. [28] compared urinary cortisol excretion in men and women during 1 wk of bed rest and reported elevated cortisol in the men only. Subsequent studies showed no change in cortisol levels in men [29, 30]. In the latter study, subjects had a 15-day pre-bed-rest period during which they were permitted to adapt to the protocol and environment. Similarly, spaceflight studies of humans showed unchanged cortisol levels after an initial adjustment period [31, 32]. Table 1 summarizes the results of studies of male reproduction utilizing ground-based models of simulated hypogravity. In humans, 6° head-down tilt bed rest for 60–120 days altered sperm morphology and reduced the number of active spermatozoa [33]. This finding has important implications because in humans even slight reductions in sperm numbers compromise reproductive capacity [34]. Bed rest had no effect on plasma T or LH but did produce a reduction in plasma FSH and prolactin levels. Both FSH and prolactin are involved in the regulation of spermatogenesis, suggesting that reductions in sperm number may have been due to simulated hypogravity-induced changes in endocrine function.
Rats exposed to simulated hypogravity using the Morey-Holton HLS model exhibited increased cortisol during initial HLS [16]. No effects have been reported on stress-inducible transcripts [4] or on adrenal gland weights [35], suggesting the absence of stress in HLS animals following initial adaptation. Congruent with the spaceflight studies, HLS rats had reduced testes weights [4, 16, 35–38]. Longer-term (>14 days) HLS of male rats resulted in >50% reductions in testes weight compared with nonsuspended controls [4, 38]. Together, these results suggest that effects on testicular weight are due to simulated hypogravity rather than stress. Atrophy of testes in HLS rats was accompanied by significant reductions in plasma T compared with nonsuspended controls and an 85% loss of spermatogenic cells [4, 38], indicating that both spermatogenesis and steroidogenesis were impaired in HLS rats.
The results of the HLS studies of T levels have generally been difficult to interpret because of the lack of standardization across studies of animals and methods for blood collection. Testosterone levels vary dramatically during testicular development in maturing rats and within normal diurnal cycles. In addition, studies of male reproduction using HLS require certain modifications because of the unique anatomical characteristics of rats. Unlike humans, the inguinal canal between the scrotum and abdominal cavity does not close in rats. Therefore, the 30° head-down angle used in the HLS model to unload the hindquarters can translocate the testes and epididymis into the abdomen. Exposing the testes to body cavity temperature results in infertility due to destruction of the germinal epithelium and death of spermatogonia [39]. Histological examination of the testes of HLS rats revealed cellular damage [3, 35], whereas preventing the testes from translocating into the abdomen by inguinal ligation resulted in no aberrant histological features in the testes and normal spermatogenesis [35]. Despite inguinal ligation, T levels remained reduced in HLS rats, and despite reduced T levels, there were no significant effects on the androgen-dependent accessory sex glands of HLS rats [35]. However, the study duration (7 days) may not have provided sufficient time for changes in the accessory sex glands to be observed.
HLS is an extremely useful model of simulated hypogravity in studies of male reproductive physiology in rats provided that care is taken to prevent translocation of the testes into the abdomen and maturational factors are taken into account. Studies using the HLS model are providing evidence that the hypogravity component of spaceflight exerts pronounced effects on male reproductive processes.
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EFFECTS OF HYPERGRAVITY ON MALE REPRODUCTION
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Centrifugation studies have enabled researchers to distinguish effects of acute versus chronic hypergravity exposure. Short-term centrifugation even at high forces of 4.1 g for 15 min had no detectable effect on the T levels of male rats [40]. However, centrifugation at 4 g for 4 h resulted in reduced T levels, suggesting that duration of exposure is important. The hypergravity experienced at lift-off and re-entry is short term; therefore, it is unlikely that the reduced T in spaceflight rats was due to acute hypergravity. Chronic centrifugation at 2 g had no effect on testes weight, T, or spermatogenesis compared with control rats [41], but 2.3 g reduced T during the initial 3 days, and 4.1 g resulted in continuous suppression of T throughout 52 days of centrifugation [40] (Table 1). These results suggest that over time, rats are capable of adapting to gravitational forces of >2.3 g but not to 4.1 g. Using centrifugation to validate the spaceflight findings has been difficult because of the pulsatile secretion of LH and elevated LH in response to disturbing stimuli such as the stopping of the centrifuge [42]. Ortiz et al. [19], avoiding the bias of daily periodicity by measuring T in 24-h urine samples, found a transient increase in urinary T in male rats centrifuged at 2 g. This finding contrasts with those of other reports of reduced T in response to centrifugation. Stress rather than hypergravity may have been responsible for elevated T, because elevated T has been reported as a response to acute stress [24]. Clearly more studies are needed, but the results of these studies suggest that hypergravity altered male reproductive hormone levels and that the response of the HPG axis depends on duration and g force.
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EFFECTS OF SPACEFLIGHT ON FEMALE REPRODUCTION
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The number of female astronauts is growing, and the presence of women on long-duration spaceflights and at the International Space Station is also expected, yet relatively little is known about the effect of spaceflight on female reproduction. Environmental conditions can exert a number of adverse effects on the ovaries. To our knowledge, no researchers have examined the effect of the space environment on the ovaries of nonpregnant females. However, examination of the ovaries of postpartum rats flown in space during Days 9–20 of gestation showed no effect on ovarian weight or number of preovulatory or atretic follicles [43]. According to Ying et al. [44], the mechanism mediating postpartum ovulation is the same as that in nonpregnant rats, suggesting that spaceflight does not affect the ovaries. Reproductive changes do not always occur at the ovaries but may occur at the hypothalamus or pituitary. The HPG axis regulates the ovulatory cycle, which is highly susceptible to environmental factors. For example, stress can lead to ovulation failure [45]. Thus, the amount of stress experienced during spaceflight might be correlated with negative effects on the ovulatory cycle, but this possibility has not been explored. No data on women have been collected because female astronauts suppress their menstrual cycles during spaceflight [5]. Animal studies of altered gravity examining ovulatory cycles are also scarce. In postpartum spaceflight rats, ovulation was suggested to be suppressed based on findings of reduced pituitary LH; however, measurement of plasma LH indicated no change. Plasma FSH was also elevated; however, there was no effect on pituitary FSH [43]. These unequivocal results are likely due to the pulsatile secretion of LH and FSH. More meaningful results would require sequential blood sampling for LH and FSH.
Serova and Denisova [46] reported that rats mated in hypogravity during spaceflight, indicating that female rats ovulated and cycled normally; however, no births resulted. Postflight laparotomies suggested that the fetuses were resorbed, but there is no clear indication of whether conception or implantation can proceed in the space environment. No systematic studies have examined the effect of spaceflight on early pregnancy. However, several spaceflight missions have included rat dams for varying durations between Days 9 and 19 of the 22-day gestation period [8, 47, 48]. The first spaceflight mission carrying pregnant mammals reported a reduction in pregnancy weight gain, prolonged parturition, lower birth weights, and increased perinatal mortality [47]. Increased neonate mortality persisted into the F2 generation. Diet, housing, and other environmental conditions peculiar to this flight may have contributed to the adverse pregnancy outcomes. Another factor may have been stress; prenatal stress is associated with increased fetal mortality, abnormal nursing behavior, and increased postnatal mortality [49, 50]. However, subsequent spaceflight studies have yielded no evidence that pregnant rats are stressed during spaceflight [8, 48].
Table 2 summarizes the results of spaceflight on female reproduction. Despite speculation that headward fluid shifts, cardiovascular deconditioning, bone demineralization, and decreased red cells associated with hypogravity may affect the ability of rat dams to sustain their pregnancy [51], the results of spaceflight studies indicate that pregnant rat dams are able to successfully direct physiological resources to support fetal development in the space environment. In females, appropriate ratios of estrogen and progesterone are required for the establishment, maintenance, and termination of pregnancy. In view of the changes in male reproductive hormones following spaceflight, there is concern that spaceflight also may affect female reproductive hormones. However, Burden et al. [43] reported no change in estrogen and progesterone levels in pregnant spaceflight rats. Spaceflight rat dams did experience an increased number of contractions during parturition due to reduced connexin 43, the major gap junction protein in the myometrium that plays a role in the synchronization and coordination of contractions [52, 53]. Although contractions in spaceflight rat dams were increased, there were no effects on fetal wastage, birth weight, litter size, or maternal care of the neonates [8]. Although progress has been made in the area of late pregnancy and neonate development, more studies are needed on fertility, conception, and early pregnancy in space. Ground-based models are well suited to address these existing gaps in our current knowledge.
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TABLE 2. Summary of the effects of spaceflight, HLS models of simulated hypogravity, and centrifugation models of hypergravity on female reproductive physiology
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EFFECTS OF SIMULATED HYPOGRAVITY ON FEMALE REPRODUCTION
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Ground-based models have not been used frequently to study the effects of hypogravity on female reproduction. Women exposed to 17 days of 6° head-down tilt bed rest showed no changes in menstrual cycle length [54] (Table 2). However, the duration of the study was too short to draw definitive conclusions. Rock and Fortney [55] reported that women exposed to bed rest exhibited luteal phase deficiency, a condition that is related to HPG axis dysfunction [56]. However, this study lacked controls. Clearly, more studies are needed to answer basic questions about female reproductive processes and to address concerns that fluid shifts associated with hypogravity may lead to retrograde menstruation or endometriosis [57, 58].
To our knowledge, no researchers have used HLS to investigate hypogravity effects on reproductive processes in nonpregnant female rats, although HLS is ideally suited to answer pertinent questions. There is no concern about the translocation of reproductive organs in female rats because the ovaries are normally situated within the abdominal area. In addition, monitoring of the ovulatory cycles of HLS female rats is a simple technique that can provide important information on ovulation, reproductive capability, HPG, and ovarian function in nonpregnant females. A few HLS studies have been conducted on pregnant rats. HLS of rats during early pregnancy reduces implantation [59]. The absence of elevated plasma or adrenal corticosterone in HLS pregnant rats suggests reproductive effects were due to simulated hypogravity exposure rather than stress [60]. Similar findings derived from the spaceflight experiments raise questions as to whether early pregnancy can be sustained in hypogravity.
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EFFECTS OF HYPERGRAVITY ON FEMALE REPRODUCTION
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Table 2 summarizes the effect of hypergravity on female reproduction. Hypergravity exposure of nonpregnant rats produced no differences in mating ability or gestation, but fewer pregnancies resulted. Hypergravity at moderate levels of 1.46 and 2.28 g disrupted the ovulatory cycle by inducing prolonged diestrus in rats [61, 62], suggesting that the reduction in the number of pregnancies observed in centrifuged rats is due to changes in the ovulatory cycles. Pregnancy did not occur in mice chronically centrifuged at 3.5 g [63]. Even centrifugation at relatively low speeds of 1.41–1.47 g resulted in an increased tendency to abort, especially during early pregnancy [64]. Serova [65] observed that centrifugation of rat dams at 2 g during early pregnancy resulted in a 33% incidence of spontaneous abortion, whereas in rats centrifuged during midpregnancy there were no cases of spontaneous abortion. These findings and the results of spaceflight studies suggest that exposure to gravitational forces different from Earth's 1 g may interfere with early pregnancy events such as implantation.
Increased mortality has been reported in neonatal rats exposed to hypergravity, even with intermittent exposure to centrifugation during the periparturition period [66]. Oyama et al. [67] reported that pregnant rat dams centrifuged at 2.16 or 3.14 g had reduced numbers of survivors within their litters compared with 1-g controls. Furthermore, neonatal mortality in this study increased with increasing g load [67]. Survival and development of neonates in hypergravity is partly dependent upon normal maternal behavior and mother-offspring interactions [68–70]. Decreased plasma prolactin in rat dams centrifuged at 2.16 or 3.14 g has been suggested as a mechanism responsible for decreased neonatal survival because prolactin plays a key role in the expression of maternal behavior in rats [71]. Because maternal care may be influenced by previous experience, Ronca et al. [70] compared primigravid and bigravid rats exposed to 1.5 g centrifugation at Gestation Days 11–22. Pup survival was 82% for primigravid dams, 94% for bigravid dams, and 99% for 1-g controls, suggesting that previous maternal experience is protective against neonatal loss [70]. These study results indicate that altered gravity affects reproductive physiology during pregnancy and lactation and affects maternal behavior and mother-offspring interactions. Further ground-based studies are needed to provide a more detailed understanding of the issues of pregnancy, birth, and rearing of offspring in space.
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EFFECTS OF ALTERED GRAVITY ON FERTILITY
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Ultimately, successful reproduction is the production of viable progeny [72]. In only one study was mating capability in the space environment examined. Rats were described as having mated successfully in hypogravity, although no viable progeny were produced [46]. It is unclear from the study design whether reproductive effects occurred in the males, the females, or both. Male spaceflight rats mated 5 days after flight to nonflight female rats bred successfully, but their offspring showed growth retardation and more frequent abnormalities, such as edema, hemorrhages, hydrocephaly, ectopic kidneys, and enlargement of the bladder [73]. Male progeny also showed reduced epididymis weight at 30 days of age, although this reduction did not persist into adulthood (100 days of age) [47]. However, male rats mated 2.5–3 mo after spaceflight produced healthy, viable offspring. Santy et al. [74] suggested that spaceflight produced abnormalities in mature sperm but had no effect on early stage sperm. Anecdotal evidence indicates that male astronauts produce healthy offspring following spaceflight. To our knowledge, fertility following recovery from HLS has not been explored. The effect of hypergravity on fertility was investigated by exposing jointly caged male and female rats to chronic centrifugation (2.3 g). Results indicated some reduction in pregnancy rate at 2 g and no successful pregnancies at 4.7 g, an extremely high g load [66]. Megory et al. [61] observed prolonged diestrus in centrifuged rats. Changes in the ovulatory cycle can compromise fertility. Reports of reduced T in centrifuged male rats [16, 19, 40] can also compromise fertility because T is important for maintaining reproductive organ function and spermatogenesis. Whether long-term exposure to altered gravity can lead to subfertility or even infertility and whether effects are temporary or permanent are important questions that must be answered before long-term habitation of space is attempted.
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CONCLUSIONS
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As the International Space Station moves us closer to the reality of space colonization, it becomes increasingly important to understand the effects of altered gravity on mammalian reproductive physiology and function. Based on the existing data, there is evidence for hypo- and hypergravity-induced changes in male and female reproductive processes. However, additional research is needed to fill in the gaps in our current knowledge. Although spaceflight experiments are critical, ground-based studies are important for the correct interpretation of spaceflight findings because spaceflight studies are often encumbered by flight restrictions and effects of environmental factors unrelated to hypogravity (i.e., radiation, vibration, noise). Research incorporating ground-based models is yielding results quite similar to those obtained from spaceflight. These similarities confirm the appropriateness of HLS, bed rest, and centrifugation for studying reproductive physiological responses and adaptation to altered gravity. Together, these unique tools are yielding new insights into the gravitational biology of reproduction in mammals.
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ACKNOWLEDGMENTS
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The authors thank Lisa Baer and Diane Yu for reviewing the manuscript.
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FOOTNOTES
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1 This research was supported by NASA grants 121-10-40, 121-10-50, and 121-40-10 and NIH grant 46485 (to C.W.). 
2 Correspondence: Charles E. Wade, Life Science Division, MS 239-11, NASA Ames Research Center, Moffett Field, CA 94035. FAX: 650 604 3954; cwade{at}mail.arc.nasa.gov
Received: 7 May 2002.
First decision: 3 June 2002.
Accepted: 7 August 2002.
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