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Human development and reproduction in space—a European perspective

Human development and reproduction in space—a European perspective www.nature.com/npjmgrav REVIEW ARTICLE OPEN Human development and reproduction in space—a European perspective 1 2 3 4 1,5 Varsha Jain , Susana M. Chuva de Sousa Lopes , Mohammed A. Benotmane , Vittore Verratti , Rod T. Mitchell and Jan-Bernd Stukenborg This review summarises key aspects of the first reproductive and developmental systems Science Community White Paper, supported by the European Space Agency (ESA). Current knowledge regarding human development and reproduction in space is mapped to the roadmap. It acknowledges that sex and gender have implications on all physiological systems, however, gender identity falls outside the scope of the document included in the white paper collection supported by ESA. The ESA SciSpacE white papers on human developmental and reproductive functions in space aim to reflect on the implications of space travel on the male and female reproductive systems, including the hypothalamic-pituitary-gonadal (HPG) reproductive hormone axis, and considerations for conception, gestation and birth. Finally, parallels are drawn as to how this may impact society as a whole on Earth. npj Microgravity (2023) 9:24 ; https://doi.org/10.1038/s41526-023-00272-5 INTRODUCTION functionality of the reproductive organs . Due to the small number of astronauts who have undertaken long duration Humans have been travelling into space for over 60 years and to spaceflight, it has not been possible to determine whether date, human conception in space has not occurred despite much spaceflight stressors or space radiation impact fertility, versus the public and media interest in the subject. Space impacts human 2–4 ageing impact which naturally affects reproductive outcomes .It physiology at every fundamental level, whether this is due to the is therefore important to gain knowledge on how increased and microgravity environment, the exposure to higher radiation doses prolonged space radiation (for short and long periods) affect the compared with being on Earth, the change in circadian rhythm functionality of female and male reproductive organs, as well as experienced during spaceflight or the stress of space travel itself. the overall impact on cancer risk, not only for the astronaut, but The overall physiological and psychological adaptation to the also their progeny and for future generations via effects on their spaceflight environment is similar for male and female astronauts; gametes. We highlight the key knowledge gaps, which apply for however, there are subtle differences detected in almost all body female and male reproductive systems, conception, embryo systems due to sex and gender. Understandably, the male and development and birth (summarised in Table 1). female reproductive systems, as they are entirely different, deserve independent focus and research to understand the short and long-term impacts of the spaceflight environment. So far, Principles of the male reproductive system there has been limited research into reproductive physiology in The majority of astronauts/cosmonauts are men. However, very relation to space travel. The ESA SciSpacE white papers set out the little is known about the effects of spaceflight on their fertility. research that will be needed to advance our knowledge in this Fertility in males is dependent on the presence of a germ cell important field of space physiology in order to support advances population, which migrate into the developing testis during the in space travel and habitation by humans . In this review, we first trimester of pregnancy. During pregnancy, the foetal germ briefly summarise the principal aspects of human development cells undergo epigenetic reprogramming and many are actively and reproduction, and relate them to studies which can be proliferating, making them susceptible to radiation. These foetal performed under space-relevant conditions. germ cells give rise to a pool of spermatogonial stem cells (SSCs) that are capable of differentiation, meiosis and development into sperm in adulthood. In adulthood, a continuous supply of sperm is KEY KNOWLEDGE GAPS OF REPRODUCTIVE FUNCTION AND achieved by maintaining a balance between SSC differentiation HUMAN DEVELOPMENT IN SPACE and self-renewal. However, the ability of SSCs to produce sperm is Currently, there is limited knowledge available on the systemic also dependent on the presence of functional somatic cell effects of spaceflight stressors, e.g. altered gravity (micro-, hypo- populations, such as supporting Sertoli cells and testosterone- and hypergravity), increased radiation, social isolation, confine- producing Leydig cells. The function of these cell populations is ment, sleep disturbances, dietary changes and any associated primarily regulated by the HPG axis . Puberty in males is initiated stress/anxiety on the hypothalamic-pituitary-gonadal (HPG) axis in from about 9 years of age and at ~13 years of age, the females and males and how these stressors impact the process of spermatogenesis results in the production of sperm 1 2 MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK. Department of Anatomy and Embryology, Leiden 3 4 University Medical Center (Building 2), Leiden, The Netherlands. Radiobiology Unit, Belgian Nuclear Research Centre ‘SCK CEN’, Mol, Belgium. Department of Psychological, 5 6 Health and Territorial Sciences, “G. d’Annunzio” University, Chieti-Pescara, Chieti, Italy. Royal Hospital for Children and Young People, Edinburgh, UK. NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, and Karolinska University Hospital, Solna, Sweden. email: jan-bernd.stukenborg@ki.se Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; V. Jain et al. Table 1. Potential priorities for future space programmes as described in the white paper collection of ESA according to previously identified key knowledge gaps, with a focus on microgravity and/or exploration relevance . Physiological changes related to human reproduction and development �‘ Sex’/‘Gender’ as well as sex steroid hormones in biological systems. � Teratogenic and oncogenic space related-effects on reproductive systems. � Foetal development of body systems in space-simulating conditions. � Age-dependent evaluation of late memory, learning and cognitive performances. � Long-term effects on gestation under space conditions. � Monitoring development and function of offspring conceived and developed in space. Male reproductive health aspects Female reproductive health aspects � Spermatogenesis relies on testicular spermatogonial stem cells, which � Hypothalamic-pituitary-ovarian-endometrial interplay is tightly require a functional stem cell niche. regulated for normal functioning � Generation of functional sperm, requires spermatogenesis, spermiogenesis, � Quantification of venous thromboembolism risk to female astronauts and final maturation processed in the epididymis. using the combined oral contraceptive pill. � Androgens are essential for development and function of the internal and � Multidisciplinary professional teams are crucial in providing external reproductive organs pregnancy and neonatal care. Timeline of potential research questions regarding reproductive health aspects Short term � How is the menstrual cycle, including age of menopause, influenced by spaceflight? � What is the impact of spaceflight on quality and competence of gametes (eggs/sperm)? � How does space travel impact gynaecological conditions in female astronauts? � What is the effect of space travel on libido and sexual attraction? Medium term � How does prolonged exposure to space radiation affect HPG axis regulation in adults? � How does menstrual suppression affect female astronauts? � What are the effects of prolonged exposure to the space environment on reproductive organs? � Can a multidisciplinary team be developed to support pregnancy and birth in space? � What is the role of hormone replacement therapy in female astronauts? Long term � How does prolonged exposure to space radiation affect HPG axis during puberty/aging? � Are there transgenerational effects on gamete quality? � Is medical assisted reproduction feasible in space? � Do female astronauts need additional monitoring during a pregnancy after space travel? � What are the effects of spaceflight during the early postpartum phase? Timeline: short [3 years], medium [5 years], long [10 years]). a 1 Ref. . (Tanner stage 4). The unique testicular microenvironment, that effects of microgravity on the reproductive function in male mice includes SSCs and supporting somatic cell populations, plays a under microgravity and artificial gravity (around 1 G) on the ISS, crucial role regulating the levels of specific growth factors and compared to mice housed on Earth as ground controls . The hormones. This makes the pre- and postnatal testis vulnerable to study showed that adult male mice housed on the ISS for 35 days disruption by environmental factors such as environmental toxins, showed, when back on Earth, no adverse effects on sperm quality radiation, and alterations in gravity (e.g. micro-, hypo- and or on the viability of their offspring . However, in a more recent 4,6–9 hypergravity) in space and on Earth . study, Yoshida and colleagues reported epigenetic alterations in sperm of adult mice housed in space (on the ISS) for 35 days . Space and the male reproductive system Here, dysregulation of 24 genes (19 upregulated and 5 down- regulated) was observed in the liver of the progeny, although The majority of studies conducted to date have used rodents and functional abnormalities in the liver of the offspring were not focused on the impact of altered gravity on spermatogenesis and reported. Additional to alterations in small RNA expression in testosterone synthesis in adulthood, in addition to radiation- spermatozoa, alterations in binding of the transcription factor related impairment of germ cell maturation and 10–12 ATF7, which binds to promotor regions in male germ cells and differentiation . Two recent studies, reported the effects on male reproductive induces methylation of histone H3 Lysine 9 (H3K9me2) suggested functions in male mice housed on the International Space Station an intergenerational effect . It can be speculated that the 13,14 (ISS) . In 2019, Matsumura and colleagues investigated the increased production of reactive oxygen species (ROS) as well as npj Microgravity (2023) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; V. Jain et al. the epigenetic alterations induced by environmental stressors (e.g. Space and the female reproductive system cosmic radiation) may contribute to dysfunction in physiological Extreme states of stress can impact the menstrual cycle on Earth ; pathways underlying HPG axis, seminal profile, and erectile however, it is unknown whether this would have the same impact function, leading to impaired male fertility. To minimise damage on natural menstrual cycles in space. Data from female astronauts to sperm by such stressors, the use of frozen-thawed sperm for who flew during the Shuttle era suggest that pregnancy rates and reproductive purposes could be one option. In a recent study, associated complication rates, are equivalent to ground-based, birth of healthy mouse pups was obtained following intra- age-matched controls . Female astronauts on long duration cytoplasmic sperm injection (ICSI) using frozen-thawed sperm missions predominantly use the combined contraceptive pill 15 27 stored for up to 5 years and 10 months on the ISS . This follow-up (COCP) to suppress menstruation and there has been so far no study from a previously reported study by the same research reported impacts on fertility rates compared to age-matched group , revealed that long-term storage of frozen-thawed sperm controls on Earth. Due to the high proportion of female astronauts using the COCP for menstrual suppression, is remains unknown in space is a potential option to store mammalian sperm for future whether the spaceflight environment impacts endometrial or use . However, future research is warranted to elucidate the 3,4 ovarian functioning . For example, it is unknown whether the details behind (epi)genetic alterations reported as well as the immune changes experienced during spaceflight have an impact impact on humans. on the immune cell populations within the endometrium, or It is well recognised that male reproductive development is whether the vasculature within the endometrium behaves in an programmed in foetal life, and is highly androgen dependent . altered manner with long-term exposure to spaceflight and Key events in postnatal life such as the mini-puberty of infancy, therefore predispose the female astronaut to abnormal bleeding testicular maturation during childhood and puberty are also patterns. Finally, with the first episode of venous thromboembo- essential for ensuring a healthy male reproductive system in lism (VTE) in space reported in 2019 , it would be important to adulthood. So far, the impacts of gravitational changes and further investigate risk factors which may impact female radiation on reproductive function from foetal life to (peri)puberty astronauts taking the COCP, a known risk factor for VTE . have not been investigated. The same applies to detailed studies There is limited data on the impact of spaceflight stressors on of effects in space beyond the low Earth orbit (e.g. on Mars), on the menstrual cycles in humans and animals; however, the SSCs and stem cell niche functions as well as germ cell maturation, simulated model of menstruation in mice provides a potential epigenetic profile, sperm quality and quantity in humans, and avenue for further research . Moreover, the effects of increased therefore warrant future studies exploring potential harmful space radiation for a prolonged period on female reproductive effects of space travel on male fertility. organs such as uterus, cervix, fallopian tubes, ovaries (which contain of the entire follicular reserve) and breasts are not well Principles of the female reproductive system studied, due to existing recommendations from national commit- According to the statistics published online tees on radiation safety that limit exposure . However, it is well (www.worldspaceflight.com/bios/stats1.php), as of November known from patients undergoing cancer treatment (radiotherapy), 2022, 639 individuals have travelled into space, out of which, 72 that oocytes are very sensitive to radiation . The overall quantity were female astronauts or cosmonauts, a mere 11%. Females and quality of oocytes (folliculogenesis takes ~50 days in mice begin puberty from approximately 8 years of age and on average and 6 months in humans ) would also need further investigation puberty completes when girls experience menarche (first period) from a fertility perspective. In this regard, it would be important to between the ages of 12–14 years (Tanner stage 4) . conduct long-term follow-up studies as a potential new platform, to investigate female reproductive health both during spaceflight and upon return to Earth, with comparisons being made with Menstrual cycle physiology ground-based, age-matched controls. This would allow both Menstruation occurs in a cyclical manner, via a delicate balance of medical and research data to be collected for both humans and hormonal stimuli, governed by the HPG axis. The predominant non-human mammals, allowing a retrospective comparison. hormones which influence menstruation within this axis are gonadotropin releasing hormone (GnRH), follicle stimulating Sex differences in space hormone (FSH) and luteinising hormone (LH), released by the It is important to define the terms sex and gender as they are brain, as well as oestradiol (E ) and progesterone (P ) secreted by 2 4 often used interchangeably, however, they have different mean- the ovary . A repetitive cycle of scarless tissue injury and repair ings, and therefore different implications when planning scientific occurs within the dynamic endometrium; this involves prolifera- research in space. The World Health Organisation defines “gender” tion, decidualisation, inflammation, apoptosis, haemostasis, vaso- as the socially constructed characteristics of women and men, constriction, hypoxia, repair and regeneration . The ovarian cycle whereas “sex” refers to biologically and physiologically deter- runs in parallel to the menstrual cycle of the uterus (the ovarian mined characteristics (https://www.who.int/health-topics/gender). follicular phase is synchronous with the endometrial menstrual Almost all body systems are impacted in their adaptation to and proliferative phase; the ovarian luteal phase is synchronous space , hence it will be important to ensure all human research with the endometrial secretory phase). roadmaps include at least both male and female astronauts in order to tease out sex differences. Sex steroid hormones The female reproductive life course (oestrogen, progesterone and androgens) have an impact on In females, the reserve of primordial follicles is determined during multiple body systems and therefore when planning studies embryonic development and these diminish continuously in including females, it would be prudent to note the menstrual cycle number and quality with age . The average age when female stage, as hormone levels can vary, and this could impact the fertility begins to decline is 32 years on Earth . The average age of results (e.g. musculoskeletal conditioning at varying time points menopause is 51 years and this signals the cessation of the during the menstrual cycle may be altered) . One example of sex- reproductive organs, in particular the ovary, functioning for the based differences relevant to spaceflight is the reduced incidence purposes of maintaining a pregnancy . Prolonged exposure to and severity of spaceflight associated neuro-ocular syndrome radiation (e.g. due to prolonged space travels) may accelerate the (SANS) in female astronauts compared to male astronauts ; decline of the follicular pool and result in premature ovarian investigating this difference and why it occurs is of importance to failure and an earlier onset of menopause . prevent long-term implications for all astronauts in the future. As Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 24 V. Jain et al. the general population is ageing and on average ISS-astronauts post-birth and this can usually be commenced via breastfeeding. are older than Shuttle era astronauts , changes associated with A multidisciplinary team of professionals may be necessary to ageing in space, including the post-menopausal years would also keep mother and baby healthy during this time; one which is not be important to monitor. Female astronauts are more susceptible readily available in space. to radiation-based cancers ; however, prevention and screening protocols for cancer in relation to astronauts who have been to From conception to birth in space space, have not been systematically implemented, e.g. would the The main safety risks for a pregnancy in space, are not only the increased radiation exposure of space necessitate an adjustment effects of excess radiation on the health of the foetus and future to the cervical or breast cancer screening which is usually baby but also the effects of space radiation on the developing undertaken by women on Earth? germ cells (future gametes of the baby) that will be used to produce the future generations. There is potential risk to their From conception to birth functionality and quality, directly influencing the health of the 14,55,56 Pregnancy is contraindicated during spaceflight and there has second generation . During mid-gestation, the developing been no recorded episodes of human conception occurring in the germ cells undergo epigenetic reprogramming as well as meiotic spaceflight environment. However, in view of a permanent Moon recombination (exclusively in female foetus), hence it will be station or the possibility of colonising other planets (e.g. Mars), important to gain knowledge on the effects of spaceflight this important aspect of human life in space needs to be stressors on the future fertility of foetuses (starting with considered alongside its associated challenges. transgenerational animal studies in space). The scarce data Conception starts when a sperm cell penetrates a competent available on rodent pregnancy and delivery rates report high mature oocyte forming the zygote. The zygote develops as it resorption and mortality both as stillbirth and during the first travels from the fallopian tube to the uterus . When inside the postnatal week. However, the pups that survived to adulthood 57,58 uterus, the embryo, known as a blastocyst, hatches and implants were able to conceive and carry viable litters . in the primed and decidualised endometrium, the inner layer of Regarding the health of the foetus itself, it has been shown that the uterus. During the following months, the placenta becomes exposure to radiation during gestation is considered highly the interface where maternal blood comes into close proximity harmful to the development of the foetus . Radiation doses with foetal blood, providing nutrients and gases to the developing equivalent to a total dose incurred during a 3-year Mars mission foetus, whilst removing waste products . During the first would lead to structural malformations in human embryos, trimester, the foetus undergoes organogenesis, with sex determi- including, microcephaly and microphthalmia as well as neural nation and the formation of the reproductive organs. This is tube defects . Effects on central nervous system (CNS) formation especially critical in the period between 6- and 14-weeks post- have been shown to lead to functional brain defects resulting in 40,41 61 conception . During organogenesis, the embryo is sensitive to low IQ and mental health impairment . Ground-based animal environmental stress (chemical, physical and viral infections), experiments confirmed the teratogenic and behavioural effects of 42–44 which may induce malformations or congenital abnormalities . radiation at different stages of gestation. Exposure during early Effects of radiation on brain development have been illustrated in organogenesis (embryonic day E7.5) in mice was shown to lead to atomic bomb survivors of Hiroshima and Nagasaki in Japan more structural malformations (exencephaly, micropthalmos/ showing high rate of malformations (microcephaly) and decreased anopthalmos) with low survival rate at 1.0 Gy X-rays, while intelligence quotient (IQ) in children that have been exposed in exposure during late organogenesis (embryonic day E10–E13) utero in the first trimester between week 8 and 15 of gestation induces both structural (microcephaly) as well as functional 45,46 49 (equivalent to 6–13 weeks post conception) . Mice exposed to (cognitive impairments) defects . radiation during the critical period of neurogenesis and brain Embryonic neuron cells cultured under space conditions using formation (between embryonic day E10 to E13) showed increase RPM (random positioning machine) and simulated radiation in apoptosis, neuroinflammation and premature neuronal differ- showed clear modulation in neuronal plasticity evidenced through 47–49 entiation , which are most-likely the major causes of micro- morphological and physiological changes. These changes were cephaly and late behaviour defects. The first trimester is also the dependent on the duration of exposure to microgravity. Significant alterations in neurite network, neuron morphology period when miscarriage rates are at their highest, which may be and viability following exposure to simulated space conditions due to environmental or genetic causes, with the specific causes frequently unknown. The maternal circulation opens to the were observed. Prolonged exposure to simulated microgravity placental (intervillous) space at the end of the first trimester , (10 days) revealed a high adaptation of neurons to the new gravity when most organs enter a period of pronounced growth conditions as well as a partial adaptation of neuronal networks. until birth. However, neurons and neuronal networks exposed for long term The average gestation period is about 37–42 weeks . Labour to simulated microgravity required longer recovery time to re- 63,64 and delivery can be associated with life-threatening situations for adapt to the ground gravity . These cellular investigations both mother and child, for example, acute haemorrhage in the indicate the harmful effect of combined space conditions mother during or after delivery or prolonged second stage of (microgravity and radiation) on maturing neuronal cells, altering labour, delaying delivery and increasing the risk of hypoxic neuronal survival, connectivity and neural network formation. ischaemic encephalopathy . It may be vital to receive acute Thus, normal brain development seems to be disturbed under medical treatment, such as a caesarean section, a blood space conditions, which would compromise brain structure and transfusion or maintaining the newborn in a neonatal intensive function at young and adult age. care unit. The first 6 weeks postpartum are critical for both mother Interestingly, folic acid food supplementation seems to be a and child. The maternal hormonal levels readjust to pre- potential radiation mitigator to counteract radiation effects in pregnancy levels and the uterus remodels to return to its pre- mice by reducing significantly the rate of malformations induced pregnancy size. Within the first minute of life, the baby must start by radiation during early organogenesis. Thus, targeted research breathing, maintain its own circulation, oxygenate its vital organs towards countermeasures and new compounds mitigating radia- and show signs of life. Usually, mother and baby have early skin- tion effects during gestation is highly required. Systematic to-skin contact, which is important for bonding, to regulate the investigations should be conducted to understand the underlying body temperature of the baby and to encourage the let-down of mechanisms behind cosmic radiation and microgravity on the 53,54 breast milk . The baby will require feeding almost immediately developing brain, and identify and develop mitigating npj Microgravity (2023) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA V. Jain et al. compounds for structural changes (malformations) as well as BENEFITS FOR EARTH AND RELEVANCE OF STUDIES functional (cognitive and behaviour) abnormalities. Moreover, CONDUCTED IN SPACE OR IN SPACE ANALOGUE ENVIRONMENTS foetal development in space with its elevated growth rate may result in high risk of increased DNA damage and genetic Female/male reproductive system mutations that could lead to abnormalities or even cancer, such Research into the reproductive organs and systems in the 66,67 as leukaemia . In this regard, the use of animal models or spaceflight environment may also provide vital information for in vitro systems (using stem cells or organoids) may shed light into Earth-based functioning and vice versa. In vitro conditions to aspects of embryonic development and help characterise the study gametogenesis have the potential to open lines of mutational load in space. investigation in space and on Earth for possible differences Another important aspect that needs further investigation is the experienced with ageing, disease, environmental pollutants or development of the maternal-foetal interface in space, especially gonadotoxic medical treatments, including radiation. Knowledge the period of implantation and placentation and its response to of the gonadotoxic effects, such as dose-dependent effects of spaceflight stressors including increased radiation. Spaceflight radiation in space, can be beneficial to identify and specify risk may cause increased oxidative stress, which has been associated factors of current or future medical treatments used on Earth. with placental dysfunction that could lead to pre-eclampsia, Developing strategies to generate functional gametes from a intrauterine growth restriction, preterm birth and gestational patient’s own germ cells (oocytes and spermatogonia) or diabetes (especially in view of the increased insulin sensitivity potentially from non-germ stem cells (e.g. induced pluripotent associated with spaceflight) . Both implantation failure and stem cells) in the laboratory via in vitro gametogenesis, can miscarriage can be influenced by nutrition, stress-related factors circumvent failure to generate competent oocytes or sperm and teratogenic medication. Although one study has reported on naturally. Recently, the combination of culture conditions spontaneous abortion among female astronauts upon returning designed for differentiating germ cells into more matured states, to Earth , longer follow-up studies and data collection are could demonstrate the differentiation of pluripotent stem cells necessary. Of high importance during pregnancy is also the (PSCs) into functional sperm in mice . In 2016, the successful additional effects of stress, nutrition and immune system reconstitution of the entire oogenic process in mice was activation. As astronauts are taking longer duration flights, they reported . These studies, together with first studies reporting may be delaying pregnancy until after their missions. It is the generation of immature human oocytes and pro- unknown whether spaceflight increases the risks of cardiovascular spermatogonia (for review see ref. ), suggest the potential to complications during pregnancy, e.g. venous thromboembolism generate functional gametes from human PSCs in the future, or pre-eclampsia, and whether extra monitoring is required during which may offer an alternative source for gamete production, subsequent pregnancies. when mature sperm or oocytes generated from natural immature Finally, throughout a pregnancy journey, a woman needs the germ cells are not available. Although promising, this technology care from a multidisciplinary team as well as tailored support at is not yet available in humans, but would be of benefit to patients key time points. Offering these in the space environment poses on Earth and would represent a major clinical advance with many challenges and these would need to be examined in further additional benefits to the industry. Should it be possible to detail to assess whether it would be possible to offer this generate competent oocytes and sperm during spaceflight multidisciplinary care in a remote/telemedicine format. conditions, these could be generated in space or in similar conditions on Earth for potential future use. Birth and first postnatal weeks in space Although the thought of childbearing in space has been 69 From conception to birth fascinating mankind for years , only very limited number of Research that advances how we keep humans healthy in space, studies have reported on the partum and postpartum effects on has the potential to generate strategies to protect pregnant rodents and the time of housing in space in these available studies 13,14 women and their unborn children on Earth. For example, the has been relatively short (15 days) . identification of compounds to counteract the harmful effects of It will be important to increase knowledge of the effects of radiation in space, could allow access to imaging or therapeutic spaceflight in the events associated with the partum and modalities for pregnant women that are currently not possible postpartum, as contradictory results have been reported, regard- due to the harmful effects of radiation. These countermeasures ing delivery, wellbeing and subsequent breastfeeding behaviour, could be administered to cancer patients prior to exposure to with direct consequences to pup mortality . Interestingly, duration radiation therapy to mitigate the effect of radiation on healthy of labour, higher number of contractions, low birth weight and tissues. In addition, such countermeasures may improve health higher mortality have been often reported . Moreover, studies on and cognition in the general population. launching rodent pups of several ages with their mothers into space, reported that 5-day and 8-day-old pups showed high mortality . Partum and postpartum Studies using pregnant rats exposed to hypergravity (1.5 G) Understanding the effects of stress factors, ionising radiation and during the second half of pregnancy and first postnatal week, resulted in increased neonatal mortality in the pups of rats changes in the inflammatory system during the early postnatal period, could be valuable to help young children on Earth (e.g. experiencing the first pregnancy, but not in the pups of rats 70,71 those with immune or vascular dysfunction). Finally, if a multi- experiencing the second pregnancy . Using animal models to increase our understanding of the disciplinary approach to provide pregnancy and postnatal care is postpartum period under microgravity and increased radiation on developed for the isolated environment of spaceflight, this would organs in particular the brain, lung, speech and locomotion as well have advantages for populations of women on Earth who live in as the limited social interaction and cognitive stimuli will be remote areas. As these women may not be able to access invaluable if we are to consider the presence of human life for antenatal and postnatal services regularly, this new telemedicine long periods of time in space. model of care could make a difference when applied on Earth. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 24 V. Jain et al. SUMMARY AND FUTURE OUTLOOK 24. Rose, B. I. Female astronauts: Impact of space radiation on menopause. Eur. J. Obstet. Gynecol. 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Human development and reproduction in space—a European perspective

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www.nature.com/npjmgrav REVIEW ARTICLE OPEN Human development and reproduction in space—a European perspective 1 2 3 4 1,5 Varsha Jain , Susana M. Chuva de Sousa Lopes , Mohammed A. Benotmane , Vittore Verratti , Rod T. Mitchell and Jan-Bernd Stukenborg This review summarises key aspects of the first reproductive and developmental systems Science Community White Paper, supported by the European Space Agency (ESA). Current knowledge regarding human development and reproduction in space is mapped to the roadmap. It acknowledges that sex and gender have implications on all physiological systems, however, gender identity falls outside the scope of the document included in the white paper collection supported by ESA. The ESA SciSpacE white papers on human developmental and reproductive functions in space aim to reflect on the implications of space travel on the male and female reproductive systems, including the hypothalamic-pituitary-gonadal (HPG) reproductive hormone axis, and considerations for conception, gestation and birth. Finally, parallels are drawn as to how this may impact society as a whole on Earth. npj Microgravity (2023) 9:24 ; https://doi.org/10.1038/s41526-023-00272-5 INTRODUCTION functionality of the reproductive organs . Due to the small number of astronauts who have undertaken long duration Humans have been travelling into space for over 60 years and to spaceflight, it has not been possible to determine whether date, human conception in space has not occurred despite much spaceflight stressors or space radiation impact fertility, versus the public and media interest in the subject. Space impacts human 2–4 ageing impact which naturally affects reproductive outcomes .It physiology at every fundamental level, whether this is due to the is therefore important to gain knowledge on how increased and microgravity environment, the exposure to higher radiation doses prolonged space radiation (for short and long periods) affect the compared with being on Earth, the change in circadian rhythm functionality of female and male reproductive organs, as well as experienced during spaceflight or the stress of space travel itself. the overall impact on cancer risk, not only for the astronaut, but The overall physiological and psychological adaptation to the also their progeny and for future generations via effects on their spaceflight environment is similar for male and female astronauts; gametes. We highlight the key knowledge gaps, which apply for however, there are subtle differences detected in almost all body female and male reproductive systems, conception, embryo systems due to sex and gender. Understandably, the male and development and birth (summarised in Table 1). female reproductive systems, as they are entirely different, deserve independent focus and research to understand the short and long-term impacts of the spaceflight environment. So far, Principles of the male reproductive system there has been limited research into reproductive physiology in The majority of astronauts/cosmonauts are men. However, very relation to space travel. The ESA SciSpacE white papers set out the little is known about the effects of spaceflight on their fertility. research that will be needed to advance our knowledge in this Fertility in males is dependent on the presence of a germ cell important field of space physiology in order to support advances population, which migrate into the developing testis during the in space travel and habitation by humans . In this review, we first trimester of pregnancy. During pregnancy, the foetal germ briefly summarise the principal aspects of human development cells undergo epigenetic reprogramming and many are actively and reproduction, and relate them to studies which can be proliferating, making them susceptible to radiation. These foetal performed under space-relevant conditions. germ cells give rise to a pool of spermatogonial stem cells (SSCs) that are capable of differentiation, meiosis and development into sperm in adulthood. In adulthood, a continuous supply of sperm is KEY KNOWLEDGE GAPS OF REPRODUCTIVE FUNCTION AND achieved by maintaining a balance between SSC differentiation HUMAN DEVELOPMENT IN SPACE and self-renewal. However, the ability of SSCs to produce sperm is Currently, there is limited knowledge available on the systemic also dependent on the presence of functional somatic cell effects of spaceflight stressors, e.g. altered gravity (micro-, hypo- populations, such as supporting Sertoli cells and testosterone- and hypergravity), increased radiation, social isolation, confine- producing Leydig cells. The function of these cell populations is ment, sleep disturbances, dietary changes and any associated primarily regulated by the HPG axis . Puberty in males is initiated stress/anxiety on the hypothalamic-pituitary-gonadal (HPG) axis in from about 9 years of age and at ~13 years of age, the females and males and how these stressors impact the process of spermatogenesis results in the production of sperm 1 2 MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK. Department of Anatomy and Embryology, Leiden 3 4 University Medical Center (Building 2), Leiden, The Netherlands. Radiobiology Unit, Belgian Nuclear Research Centre ‘SCK CEN’, Mol, Belgium. Department of Psychological, 5 6 Health and Territorial Sciences, “G. d’Annunzio” University, Chieti-Pescara, Chieti, Italy. Royal Hospital for Children and Young People, Edinburgh, UK. NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, and Karolinska University Hospital, Solna, Sweden. email: jan-bernd.stukenborg@ki.se Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; V. Jain et al. Table 1. Potential priorities for future space programmes as described in the white paper collection of ESA according to previously identified key knowledge gaps, with a focus on microgravity and/or exploration relevance . Physiological changes related to human reproduction and development �‘ Sex’/‘Gender’ as well as sex steroid hormones in biological systems. � Teratogenic and oncogenic space related-effects on reproductive systems. � Foetal development of body systems in space-simulating conditions. � Age-dependent evaluation of late memory, learning and cognitive performances. � Long-term effects on gestation under space conditions. � Monitoring development and function of offspring conceived and developed in space. Male reproductive health aspects Female reproductive health aspects � Spermatogenesis relies on testicular spermatogonial stem cells, which � Hypothalamic-pituitary-ovarian-endometrial interplay is tightly require a functional stem cell niche. regulated for normal functioning � Generation of functional sperm, requires spermatogenesis, spermiogenesis, � Quantification of venous thromboembolism risk to female astronauts and final maturation processed in the epididymis. using the combined oral contraceptive pill. � Androgens are essential for development and function of the internal and � Multidisciplinary professional teams are crucial in providing external reproductive organs pregnancy and neonatal care. Timeline of potential research questions regarding reproductive health aspects Short term � How is the menstrual cycle, including age of menopause, influenced by spaceflight? � What is the impact of spaceflight on quality and competence of gametes (eggs/sperm)? � How does space travel impact gynaecological conditions in female astronauts? � What is the effect of space travel on libido and sexual attraction? Medium term � How does prolonged exposure to space radiation affect HPG axis regulation in adults? � How does menstrual suppression affect female astronauts? � What are the effects of prolonged exposure to the space environment on reproductive organs? � Can a multidisciplinary team be developed to support pregnancy and birth in space? � What is the role of hormone replacement therapy in female astronauts? Long term � How does prolonged exposure to space radiation affect HPG axis during puberty/aging? � Are there transgenerational effects on gamete quality? � Is medical assisted reproduction feasible in space? � Do female astronauts need additional monitoring during a pregnancy after space travel? � What are the effects of spaceflight during the early postpartum phase? Timeline: short [3 years], medium [5 years], long [10 years]). a 1 Ref. . (Tanner stage 4). The unique testicular microenvironment, that effects of microgravity on the reproductive function in male mice includes SSCs and supporting somatic cell populations, plays a under microgravity and artificial gravity (around 1 G) on the ISS, crucial role regulating the levels of specific growth factors and compared to mice housed on Earth as ground controls . The hormones. This makes the pre- and postnatal testis vulnerable to study showed that adult male mice housed on the ISS for 35 days disruption by environmental factors such as environmental toxins, showed, when back on Earth, no adverse effects on sperm quality radiation, and alterations in gravity (e.g. micro-, hypo- and or on the viability of their offspring . However, in a more recent 4,6–9 hypergravity) in space and on Earth . study, Yoshida and colleagues reported epigenetic alterations in sperm of adult mice housed in space (on the ISS) for 35 days . Space and the male reproductive system Here, dysregulation of 24 genes (19 upregulated and 5 down- regulated) was observed in the liver of the progeny, although The majority of studies conducted to date have used rodents and functional abnormalities in the liver of the offspring were not focused on the impact of altered gravity on spermatogenesis and reported. Additional to alterations in small RNA expression in testosterone synthesis in adulthood, in addition to radiation- spermatozoa, alterations in binding of the transcription factor related impairment of germ cell maturation and 10–12 ATF7, which binds to promotor regions in male germ cells and differentiation . Two recent studies, reported the effects on male reproductive induces methylation of histone H3 Lysine 9 (H3K9me2) suggested functions in male mice housed on the International Space Station an intergenerational effect . It can be speculated that the 13,14 (ISS) . In 2019, Matsumura and colleagues investigated the increased production of reactive oxygen species (ROS) as well as npj Microgravity (2023) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; V. Jain et al. the epigenetic alterations induced by environmental stressors (e.g. Space and the female reproductive system cosmic radiation) may contribute to dysfunction in physiological Extreme states of stress can impact the menstrual cycle on Earth ; pathways underlying HPG axis, seminal profile, and erectile however, it is unknown whether this would have the same impact function, leading to impaired male fertility. To minimise damage on natural menstrual cycles in space. Data from female astronauts to sperm by such stressors, the use of frozen-thawed sperm for who flew during the Shuttle era suggest that pregnancy rates and reproductive purposes could be one option. In a recent study, associated complication rates, are equivalent to ground-based, birth of healthy mouse pups was obtained following intra- age-matched controls . Female astronauts on long duration cytoplasmic sperm injection (ICSI) using frozen-thawed sperm missions predominantly use the combined contraceptive pill 15 27 stored for up to 5 years and 10 months on the ISS . This follow-up (COCP) to suppress menstruation and there has been so far no study from a previously reported study by the same research reported impacts on fertility rates compared to age-matched group , revealed that long-term storage of frozen-thawed sperm controls on Earth. Due to the high proportion of female astronauts using the COCP for menstrual suppression, is remains unknown in space is a potential option to store mammalian sperm for future whether the spaceflight environment impacts endometrial or use . However, future research is warranted to elucidate the 3,4 ovarian functioning . For example, it is unknown whether the details behind (epi)genetic alterations reported as well as the immune changes experienced during spaceflight have an impact impact on humans. on the immune cell populations within the endometrium, or It is well recognised that male reproductive development is whether the vasculature within the endometrium behaves in an programmed in foetal life, and is highly androgen dependent . altered manner with long-term exposure to spaceflight and Key events in postnatal life such as the mini-puberty of infancy, therefore predispose the female astronaut to abnormal bleeding testicular maturation during childhood and puberty are also patterns. Finally, with the first episode of venous thromboembo- essential for ensuring a healthy male reproductive system in lism (VTE) in space reported in 2019 , it would be important to adulthood. So far, the impacts of gravitational changes and further investigate risk factors which may impact female radiation on reproductive function from foetal life to (peri)puberty astronauts taking the COCP, a known risk factor for VTE . have not been investigated. The same applies to detailed studies There is limited data on the impact of spaceflight stressors on of effects in space beyond the low Earth orbit (e.g. on Mars), on the menstrual cycles in humans and animals; however, the SSCs and stem cell niche functions as well as germ cell maturation, simulated model of menstruation in mice provides a potential epigenetic profile, sperm quality and quantity in humans, and avenue for further research . Moreover, the effects of increased therefore warrant future studies exploring potential harmful space radiation for a prolonged period on female reproductive effects of space travel on male fertility. organs such as uterus, cervix, fallopian tubes, ovaries (which contain of the entire follicular reserve) and breasts are not well Principles of the female reproductive system studied, due to existing recommendations from national commit- According to the statistics published online tees on radiation safety that limit exposure . However, it is well (www.worldspaceflight.com/bios/stats1.php), as of November known from patients undergoing cancer treatment (radiotherapy), 2022, 639 individuals have travelled into space, out of which, 72 that oocytes are very sensitive to radiation . The overall quantity were female astronauts or cosmonauts, a mere 11%. Females and quality of oocytes (folliculogenesis takes ~50 days in mice begin puberty from approximately 8 years of age and on average and 6 months in humans ) would also need further investigation puberty completes when girls experience menarche (first period) from a fertility perspective. In this regard, it would be important to between the ages of 12–14 years (Tanner stage 4) . conduct long-term follow-up studies as a potential new platform, to investigate female reproductive health both during spaceflight and upon return to Earth, with comparisons being made with Menstrual cycle physiology ground-based, age-matched controls. This would allow both Menstruation occurs in a cyclical manner, via a delicate balance of medical and research data to be collected for both humans and hormonal stimuli, governed by the HPG axis. The predominant non-human mammals, allowing a retrospective comparison. hormones which influence menstruation within this axis are gonadotropin releasing hormone (GnRH), follicle stimulating Sex differences in space hormone (FSH) and luteinising hormone (LH), released by the It is important to define the terms sex and gender as they are brain, as well as oestradiol (E ) and progesterone (P ) secreted by 2 4 often used interchangeably, however, they have different mean- the ovary . A repetitive cycle of scarless tissue injury and repair ings, and therefore different implications when planning scientific occurs within the dynamic endometrium; this involves prolifera- research in space. The World Health Organisation defines “gender” tion, decidualisation, inflammation, apoptosis, haemostasis, vaso- as the socially constructed characteristics of women and men, constriction, hypoxia, repair and regeneration . The ovarian cycle whereas “sex” refers to biologically and physiologically deter- runs in parallel to the menstrual cycle of the uterus (the ovarian mined characteristics (https://www.who.int/health-topics/gender). follicular phase is synchronous with the endometrial menstrual Almost all body systems are impacted in their adaptation to and proliferative phase; the ovarian luteal phase is synchronous space , hence it will be important to ensure all human research with the endometrial secretory phase). roadmaps include at least both male and female astronauts in order to tease out sex differences. Sex steroid hormones The female reproductive life course (oestrogen, progesterone and androgens) have an impact on In females, the reserve of primordial follicles is determined during multiple body systems and therefore when planning studies embryonic development and these diminish continuously in including females, it would be prudent to note the menstrual cycle number and quality with age . The average age when female stage, as hormone levels can vary, and this could impact the fertility begins to decline is 32 years on Earth . The average age of results (e.g. musculoskeletal conditioning at varying time points menopause is 51 years and this signals the cessation of the during the menstrual cycle may be altered) . One example of sex- reproductive organs, in particular the ovary, functioning for the based differences relevant to spaceflight is the reduced incidence purposes of maintaining a pregnancy . Prolonged exposure to and severity of spaceflight associated neuro-ocular syndrome radiation (e.g. due to prolonged space travels) may accelerate the (SANS) in female astronauts compared to male astronauts ; decline of the follicular pool and result in premature ovarian investigating this difference and why it occurs is of importance to failure and an earlier onset of menopause . prevent long-term implications for all astronauts in the future. As Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 24 V. Jain et al. the general population is ageing and on average ISS-astronauts post-birth and this can usually be commenced via breastfeeding. are older than Shuttle era astronauts , changes associated with A multidisciplinary team of professionals may be necessary to ageing in space, including the post-menopausal years would also keep mother and baby healthy during this time; one which is not be important to monitor. Female astronauts are more susceptible readily available in space. to radiation-based cancers ; however, prevention and screening protocols for cancer in relation to astronauts who have been to From conception to birth in space space, have not been systematically implemented, e.g. would the The main safety risks for a pregnancy in space, are not only the increased radiation exposure of space necessitate an adjustment effects of excess radiation on the health of the foetus and future to the cervical or breast cancer screening which is usually baby but also the effects of space radiation on the developing undertaken by women on Earth? germ cells (future gametes of the baby) that will be used to produce the future generations. There is potential risk to their From conception to birth functionality and quality, directly influencing the health of the 14,55,56 Pregnancy is contraindicated during spaceflight and there has second generation . During mid-gestation, the developing been no recorded episodes of human conception occurring in the germ cells undergo epigenetic reprogramming as well as meiotic spaceflight environment. However, in view of a permanent Moon recombination (exclusively in female foetus), hence it will be station or the possibility of colonising other planets (e.g. Mars), important to gain knowledge on the effects of spaceflight this important aspect of human life in space needs to be stressors on the future fertility of foetuses (starting with considered alongside its associated challenges. transgenerational animal studies in space). The scarce data Conception starts when a sperm cell penetrates a competent available on rodent pregnancy and delivery rates report high mature oocyte forming the zygote. The zygote develops as it resorption and mortality both as stillbirth and during the first travels from the fallopian tube to the uterus . When inside the postnatal week. However, the pups that survived to adulthood 57,58 uterus, the embryo, known as a blastocyst, hatches and implants were able to conceive and carry viable litters . in the primed and decidualised endometrium, the inner layer of Regarding the health of the foetus itself, it has been shown that the uterus. During the following months, the placenta becomes exposure to radiation during gestation is considered highly the interface where maternal blood comes into close proximity harmful to the development of the foetus . Radiation doses with foetal blood, providing nutrients and gases to the developing equivalent to a total dose incurred during a 3-year Mars mission foetus, whilst removing waste products . During the first would lead to structural malformations in human embryos, trimester, the foetus undergoes organogenesis, with sex determi- including, microcephaly and microphthalmia as well as neural nation and the formation of the reproductive organs. This is tube defects . Effects on central nervous system (CNS) formation especially critical in the period between 6- and 14-weeks post- have been shown to lead to functional brain defects resulting in 40,41 61 conception . During organogenesis, the embryo is sensitive to low IQ and mental health impairment . Ground-based animal environmental stress (chemical, physical and viral infections), experiments confirmed the teratogenic and behavioural effects of 42–44 which may induce malformations or congenital abnormalities . radiation at different stages of gestation. Exposure during early Effects of radiation on brain development have been illustrated in organogenesis (embryonic day E7.5) in mice was shown to lead to atomic bomb survivors of Hiroshima and Nagasaki in Japan more structural malformations (exencephaly, micropthalmos/ showing high rate of malformations (microcephaly) and decreased anopthalmos) with low survival rate at 1.0 Gy X-rays, while intelligence quotient (IQ) in children that have been exposed in exposure during late organogenesis (embryonic day E10–E13) utero in the first trimester between week 8 and 15 of gestation induces both structural (microcephaly) as well as functional 45,46 49 (equivalent to 6–13 weeks post conception) . Mice exposed to (cognitive impairments) defects . radiation during the critical period of neurogenesis and brain Embryonic neuron cells cultured under space conditions using formation (between embryonic day E10 to E13) showed increase RPM (random positioning machine) and simulated radiation in apoptosis, neuroinflammation and premature neuronal differ- showed clear modulation in neuronal plasticity evidenced through 47–49 entiation , which are most-likely the major causes of micro- morphological and physiological changes. These changes were cephaly and late behaviour defects. The first trimester is also the dependent on the duration of exposure to microgravity. Significant alterations in neurite network, neuron morphology period when miscarriage rates are at their highest, which may be and viability following exposure to simulated space conditions due to environmental or genetic causes, with the specific causes frequently unknown. The maternal circulation opens to the were observed. Prolonged exposure to simulated microgravity placental (intervillous) space at the end of the first trimester , (10 days) revealed a high adaptation of neurons to the new gravity when most organs enter a period of pronounced growth conditions as well as a partial adaptation of neuronal networks. until birth. However, neurons and neuronal networks exposed for long term The average gestation period is about 37–42 weeks . Labour to simulated microgravity required longer recovery time to re- 63,64 and delivery can be associated with life-threatening situations for adapt to the ground gravity . These cellular investigations both mother and child, for example, acute haemorrhage in the indicate the harmful effect of combined space conditions mother during or after delivery or prolonged second stage of (microgravity and radiation) on maturing neuronal cells, altering labour, delaying delivery and increasing the risk of hypoxic neuronal survival, connectivity and neural network formation. ischaemic encephalopathy . It may be vital to receive acute Thus, normal brain development seems to be disturbed under medical treatment, such as a caesarean section, a blood space conditions, which would compromise brain structure and transfusion or maintaining the newborn in a neonatal intensive function at young and adult age. care unit. The first 6 weeks postpartum are critical for both mother Interestingly, folic acid food supplementation seems to be a and child. The maternal hormonal levels readjust to pre- potential radiation mitigator to counteract radiation effects in pregnancy levels and the uterus remodels to return to its pre- mice by reducing significantly the rate of malformations induced pregnancy size. Within the first minute of life, the baby must start by radiation during early organogenesis. Thus, targeted research breathing, maintain its own circulation, oxygenate its vital organs towards countermeasures and new compounds mitigating radia- and show signs of life. Usually, mother and baby have early skin- tion effects during gestation is highly required. Systematic to-skin contact, which is important for bonding, to regulate the investigations should be conducted to understand the underlying body temperature of the baby and to encourage the let-down of mechanisms behind cosmic radiation and microgravity on the 53,54 breast milk . The baby will require feeding almost immediately developing brain, and identify and develop mitigating npj Microgravity (2023) 24 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA V. Jain et al. compounds for structural changes (malformations) as well as BENEFITS FOR EARTH AND RELEVANCE OF STUDIES functional (cognitive and behaviour) abnormalities. Moreover, CONDUCTED IN SPACE OR IN SPACE ANALOGUE ENVIRONMENTS foetal development in space with its elevated growth rate may result in high risk of increased DNA damage and genetic Female/male reproductive system mutations that could lead to abnormalities or even cancer, such Research into the reproductive organs and systems in the 66,67 as leukaemia . In this regard, the use of animal models or spaceflight environment may also provide vital information for in vitro systems (using stem cells or organoids) may shed light into Earth-based functioning and vice versa. In vitro conditions to aspects of embryonic development and help characterise the study gametogenesis have the potential to open lines of mutational load in space. investigation in space and on Earth for possible differences Another important aspect that needs further investigation is the experienced with ageing, disease, environmental pollutants or development of the maternal-foetal interface in space, especially gonadotoxic medical treatments, including radiation. Knowledge the period of implantation and placentation and its response to of the gonadotoxic effects, such as dose-dependent effects of spaceflight stressors including increased radiation. Spaceflight radiation in space, can be beneficial to identify and specify risk may cause increased oxidative stress, which has been associated factors of current or future medical treatments used on Earth. with placental dysfunction that could lead to pre-eclampsia, Developing strategies to generate functional gametes from a intrauterine growth restriction, preterm birth and gestational patient’s own germ cells (oocytes and spermatogonia) or diabetes (especially in view of the increased insulin sensitivity potentially from non-germ stem cells (e.g. induced pluripotent associated with spaceflight) . Both implantation failure and stem cells) in the laboratory via in vitro gametogenesis, can miscarriage can be influenced by nutrition, stress-related factors circumvent failure to generate competent oocytes or sperm and teratogenic medication. Although one study has reported on naturally. Recently, the combination of culture conditions spontaneous abortion among female astronauts upon returning designed for differentiating germ cells into more matured states, to Earth , longer follow-up studies and data collection are could demonstrate the differentiation of pluripotent stem cells necessary. Of high importance during pregnancy is also the (PSCs) into functional sperm in mice . In 2016, the successful additional effects of stress, nutrition and immune system reconstitution of the entire oogenic process in mice was activation. As astronauts are taking longer duration flights, they reported . These studies, together with first studies reporting may be delaying pregnancy until after their missions. It is the generation of immature human oocytes and pro- unknown whether spaceflight increases the risks of cardiovascular spermatogonia (for review see ref. ), suggest the potential to complications during pregnancy, e.g. venous thromboembolism generate functional gametes from human PSCs in the future, or pre-eclampsia, and whether extra monitoring is required during which may offer an alternative source for gamete production, subsequent pregnancies. when mature sperm or oocytes generated from natural immature Finally, throughout a pregnancy journey, a woman needs the germ cells are not available. Although promising, this technology care from a multidisciplinary team as well as tailored support at is not yet available in humans, but would be of benefit to patients key time points. Offering these in the space environment poses on Earth and would represent a major clinical advance with many challenges and these would need to be examined in further additional benefits to the industry. Should it be possible to detail to assess whether it would be possible to offer this generate competent oocytes and sperm during spaceflight multidisciplinary care in a remote/telemedicine format. conditions, these could be generated in space or in similar conditions on Earth for potential future use. Birth and first postnatal weeks in space Although the thought of childbearing in space has been 69 From conception to birth fascinating mankind for years , only very limited number of Research that advances how we keep humans healthy in space, studies have reported on the partum and postpartum effects on has the potential to generate strategies to protect pregnant rodents and the time of housing in space in these available studies 13,14 women and their unborn children on Earth. For example, the has been relatively short (15 days) . identification of compounds to counteract the harmful effects of It will be important to increase knowledge of the effects of radiation in space, could allow access to imaging or therapeutic spaceflight in the events associated with the partum and modalities for pregnant women that are currently not possible postpartum, as contradictory results have been reported, regard- due to the harmful effects of radiation. These countermeasures ing delivery, wellbeing and subsequent breastfeeding behaviour, could be administered to cancer patients prior to exposure to with direct consequences to pup mortality . Interestingly, duration radiation therapy to mitigate the effect of radiation on healthy of labour, higher number of contractions, low birth weight and tissues. In addition, such countermeasures may improve health higher mortality have been often reported . Moreover, studies on and cognition in the general population. launching rodent pups of several ages with their mothers into space, reported that 5-day and 8-day-old pups showed high mortality . Partum and postpartum Studies using pregnant rats exposed to hypergravity (1.5 G) Understanding the effects of stress factors, ionising radiation and during the second half of pregnancy and first postnatal week, resulted in increased neonatal mortality in the pups of rats changes in the inflammatory system during the early postnatal period, could be valuable to help young children on Earth (e.g. experiencing the first pregnancy, but not in the pups of rats 70,71 those with immune or vascular dysfunction). Finally, if a multi- experiencing the second pregnancy . Using animal models to increase our understanding of the disciplinary approach to provide pregnancy and postnatal care is postpartum period under microgravity and increased radiation on developed for the isolated environment of spaceflight, this would organs in particular the brain, lung, speech and locomotion as well have advantages for populations of women on Earth who live in as the limited social interaction and cognitive stimuli will be remote areas. As these women may not be able to access invaluable if we are to consider the presence of human life for antenatal and postnatal services regularly, this new telemedicine long periods of time in space. model of care could make a difference when applied on Earth. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 24 V. Jain et al. SUMMARY AND FUTURE OUTLOOK 24. Rose, B. I. Female astronauts: Impact of space radiation on menopause. Eur. J. Obstet. Gynecol. 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Gynecol. material in this article are included in the article’s Creative Commons license, unless Neonatal Nurs. 19, 344–349 (1990). indicated otherwise in a credit line to the material. If material is not included in the 70. Lintault, L. M. et al. In a hypergravity environment neonatal survival is adversely article’s Creative Commons license and your intended use is not permitted by statutory affected by alterations in dam tissue metabolism rather than reduced food regulation or exceeds the permitted use, you will need to obtain permission directly intake. J. Appl. Physiol. (1985) 102, 2186–2193 (2007). from the copyright holder. To view a copy of this license, visit http:// 71. Ronca, A. E., Baer, L. A., Daunton, N. G. & Wade, C. E. Maternal reproductive creativecommons.org/licenses/by/4.0/. experience enhances early postnatal outcome following gestation and birth of rats in hypergravity. Biol. Reprod. 65, 805–813 (2001). 72. Ishikura, Y. et al. In vitro reconstitution of the whole male germ-cell development © The Author(s) 2023 from mouse pluripotent stem cells. Cell Stem Cell 28, 2167–2179 e2169 (2021). Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 24

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