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Maternal oxygen administration and fetal cerebral oxygenation: studies on near-term fetal lambs at both low and high altitude.

OBJECTIVE: We tested the hypothesis that O2 administration to the mother would increase arterial O2 tension (PaO2) and cortical tissue O2 tension (tPO2) in both the normoxic control fetus and that acclimatized to high altitude, and that this effect might be greater in the high altitude fetus than that at sea level. STUDY DESIGN: Pregnant ewes were divided into either low-altitude group or high-altitude group (3820 m; maintained from day 30 of gestation to near-term, term = 145 days; n = 6 each). In near-term fetuses we instrumented the cerebral cortex with tissue PO2-laser Doppler flow probes, and placed arterial catheters. With the ewe breathing either air or 50% O2, we measured fetal arterial and brain tissue PO2 and cerebral blood flow (CBF). RESULTS: In response to maternal O2 administration, in both low- and high-altitude fetuses, PaO2, O2 content, and brain tissue PO2 increased significantly. Nonetheless, the fetuses at high altitude showed significantly greater increase in both PaO2 and cerebral tPO2, than that seen in fetuses at low altitude. In neither group was there a change in CBF or cerebral metabolic rate for O2. CONCLUSION: Maternal O2 administration significantly increased PaO2 and cerebral tPO2 of the fetus both at low altitude and at high altitude, with this increase being greater in the high altitude animals. We suggest that maternal O2 administration can have an important effect in ameliorating nonreassuring fetal status, and perhaps be of value in instances of mothers who smoke heavily or with cardiopulmonary disease.

Acclimatization↗

High altitude-induced pulmonary oedema.

Almost one mountain trekker or climber out of two develops several symptoms of high altitude illness after a rapid ascent (> 300 m/day) to an altitude above 4000 m. Individual susceptibility is the most important determinant for the occurrence of high altitude pulmonary oedema (HAPE). Symptoms associated with HAPE are incapacitating fatigue, chest tightness, dyspnoea at the slightest effort, orthopnoea, and cough with due to haemoptysis in an advanced stage of the disease pink frothy sputum. The hallmark of HAPE is an excessively elevated pulmonary artery pressure (mean pressures of 35 and 55 mm Hg), which precedes the development of pulmonary oedema. Elevated pulmonary capillary pressure and protein- as well as red blood cell-rich oedema fluid without signs of inflammation in its early stage are characteristic findings. Furthermore, decreased fluid clearance from the alveoli may contribute to this non-cardiogenic pulmonary oedema. Immediate descent or supplemental oxygen and nifedipine are recommended until descent is possible. Susceptible individuals can prevent HAPE by slow ascent: an average gain of altitude not exceeding 400 m/day above an altitude of 2500 m. If progressive high altitude acclimatization is not possible, a prophylaxis with nifedipine should be recommended.

Acclimatization↗

Seasonal and daily changes in the capacity for nonshivering thermogenesis in the golden hamsters housed under semi-natural conditions.

Nonshivering thermogenesis (NST) is a main source of heat for many small mammals. It undergoes seasonal changes, being the highest in winter and the lowest in summer. Such acclimatization can ensure winter survival for species living in moderate or cold climates. Nevertheless, not only seasonal, but also daily changes in the capacity for NST seem to be of great importance. In this study, the effects of season and time of day on the temperature of brown adipose tissue (T(BAT)), preferred ambient temperature (PT(a)) and activity after noradrenaline (NA) injections in golden hamsters (Mesocricetus auratus) housed under semi-natural conditions were investigated. Animals were kept in outdoor enclosures and experienced natural changes in both, photoperiod and ambient temperature (T(a)). NA-induced hyperthermia was the largest during autumn (mean increase in T(BAT) by 0.74+/-0.04 degrees C), while during summer increase in T(BAT) was similar to that recorded in control (saline-injected) animals (0.16+/-0.05 degrees C and 0.24+/-0.04 degrees C, respectively). In spring hyperthermia was intermediary (0.57+/-0.05 degrees C). Daily variations in the response to NA depended on the season. In summer, the largest increase in T(BAT) (0.45+/-0.1 degrees C) was recorded during the first part of the day, while in autumn-in the middle of the day and night (1.1+/-0.1 degrees C and 0.9+/-0.1 degrees C, respectively). In spring, all NA injections induced large increase in T(BAT) except for the injection in the middle of the night. The largest decrease in PT(a) after NA administration was recorded in autumn (mean decrease by 1.5+/-0.3 degrees C). Both, seasonal and daily changes in the capacity for NST reflect different demands for heat dependently on the time of the year and time of the day. It can be concluded that although long history of breeding in captivity, golden hamsters preserved ability to survive in natural environment.

Acclimatization↗

Thermal acclimation and seasonal variations of erythrocyte size in the Andean mouse Phyllotis xanthopygus rupestris.

Seasonal hematological adjustments in small mammals may include changes in the number and size of the red cells or changes in other linked blood parameters. The direction and magnitude of these changes vary in different species. We hypothesized that the observed variations of the red cell adjustments could be directly related to the magnitude of the seasonal temperature differential, and predicted that the annual red cell size variation in rodents from environments with marked seasonal changes would tend to disappear, if the animals were raised under milder and constant environments. To test this idea, we got field blood samples from the Andean species Phyllotis xanthopygus rupestris enduring a winter-summer thermal differential of at least 20 degrees C. These animals had significantly smaller erythrocytes during the winter. Contrary to our prediction, their offspring born and raised under constant temperature conditions showed a similar trend. Unless the effective environmental cue differed from the one we used, these results favor the idea of a genetically determined annual red cell size variation that occurs independent of thermal acclimation and acclimatization.

Acclimatization↗

Increased hypoxic ventilatory response during 8 weeks at 3800 m altitude.

Acclimatization to chronic hypoxia (CH) increases ventilation (V(I)) and the isocapnic hypoxic ventilatory response (HVR) over 2-14 days but hypoxic desensitization blunts the HVR after years of CH. We tested for hypoxic desensitization during the first 2 months of CH by studying five normal subjects at sea level (SL) and for 8 weeks at 3800 m (CH, PI(O(2)) approximately 90 Torr). We measured the isocapnic HVR (Delta V(I)/Delta Sa(O(2)) and tested for hypoxic ventilatory decline (HVD) by stepping Sa(O(2)) to 80% after 14 min at 90%. The HVR increased significantly after 2 days and remained significantly elevated for 8 weeks of CH. HVD was similar at SL and during 8 weeks of CH. Hence, hypoxic desensitization of the HVR does not occur after only 8 weeks of hypoxia and the increased HVR during this time does not involve changes in HVD.

Acclimatization↗

Jack Reeves and his science.

John T. (Jack) Reeves' science is reviewed across the 37 years of his research career at the University of Colorado Health Sciences Center, a period which occupied approximately half his remarkable life. His contributions centered on understanding the inter-relatedness as well as the underlying mechanisms controlling the various components of the O(2) transport system. We review here his studies on exercise performance; these encompassed about half his scientific output with the other half being devoted to the study of hypoxic pulmonary hypertension. Early studies concerned cardiac output, showing how it was a balance between O(2) uptake and O(2) extraction, and that cardiac output during exercise at high altitude was reduced, most likely because of decreased plasma volume and left ventricular filling. Jack's many studies addressed virtually every aspect of the O(2) transport system -- adding significantly to our understanding of the syndromes of altitude illness, the mechanisms by which ventilatory sensitivity to hypoxia and hypercapnia influenced ventilatory acclimatization, and the contributions of the various limbs of the autonomic nervous system on systemic blood pressure, vascular resistance and substrate utilization. His scientific career ended abruptly in 2004 when struck by a car while biking to work, but his legacy remains in his more than 385+ research articles or chapters, the 40+ fellows he trained, and the countless number of younger (and older) scientists for whom he served as a role model for learning how to scrutinize their data and present their findings in clear and sometimes bold prose. An integral man, he is sorely missed.

Acclimatization↗

Osmoregulatory and metabolic changes in the gilthead sea bream Sparus auratus after arginine vasotocin (AVT) treatment.

The influence of arginine vasotocin (AVT) on osmoregulation and metabolism in gilthead sea bream Sparus auratus was evaluated by two experimental approaches. In the first, seawater (SW, 36 ppt)-acclimatized fish were injected intraperitoneally with vehicle (vegetable oil) or two doses of AVT (0.5 and 1 microg/g body weight). Twenty-four hours later, eight fish from each group were sampled; the remaining fish were transferred to low saline water (LSW, 6 ppt, hypoosmotic test), SW (transfer control), and hypersaline water (HSW, 55 ppt, hyperosmotic test). After another 24h (48-h post-injection), fish were sampled. The only significant effect observed was the increase of sodium levels in AVT-treated fish transferred to HSW. In the second experiment, fish were injected intraperitoneally with slow-release vegetable oil implants (mixture 1:1 of coconut oil and seeds oil) alone or containing AVT (1 microg/g body weight). After 3 days, eight fish from each group were sampled; the remaining fish were transferred to LSW, SW, and HSW as above, and sampled 3 days later (i.e. 6 days post-injection). In the AVT-treated group transferred from SW to SW, a significant increase vs. control was observed in gill Na(+),K(+)-ATPase activity. Kidney Na(+),K(+)-ATPase activity decreased in the AVT-treated group transferred to LSW and no changes were observed in the other groups. These osmoregulatory changes suggest a role for AVT during hyperosmotic acclimation based on changes displayed by gill Na(+),K(+)-ATPase activity. AVT treatment increased plasma cortisol levels in fish transferred to LSW and HSW. In addition, AVT treatment affected parameters of carbohydrate, lipid, amino acid, and lactate metabolism in plasma and tissues (gills, kidney, liver, and brain). The most relevant effects were the increased potential of liver for glycogen mobilization and glucose release resulting in increased plasma levels of glucose in AVT-treated fish transferred to LSW and HSW. These changes may be related to the energy repartitioning process occurring during osmotic adaptation of S. auratus to extreme environmental salinities and could be mediated by increased levels of cortisol in plasma.

Acclimatization↗

Control of Cl- transport in the operculum epithelium of Fundulus heteroclitus: long- and short-term salinity adaptation.

The eurohaline fish, Fundulus heteroclitus, adapts rapidly to enhanced salinity by increasing the ion secretion by gill chloride cells. An increase of approximately 70 mOsm in plasma osmolarity was previously found during the transition. To mimic this in vitro, isolated opercular epithelia of seawater-adapted Fundulus mounted in a modified Ussing chamber were exposed to an increase in NaCl and/or osmolarity on the basolateral side, which immediately increased I(SC). Various Cl(-) channel blockers as well as the K(+) channel blocker Ba(2+) added to the basolateral side all inhibited the steady-state as well as the hypertonic stimulation of I(SC). The exists -agonist isoproterenol stimulates I(SC) in standard Ringer solutions. In contrast, when cell volume was kept at the larger value by simultaneous addition of water, the stimulation with isoproterenol was abolished, suggesting that the key process for activation of the Na(+), K(+), 2Cl(-) cotransporter is cell shrinkage. The protein kinase C (PKC) inhibitor chelerythrine and the myosin light chain kinase (MLCK) inhibitor ML-7 had strong inhibitory effects on the mannitol activation of I(SC), thus both MLCK and PKC are involved. The two specific protein kinase A (PKA) inhibitors H-89 and KT 5720 had no effect after mannitol addition whereas isoproterenol stimulation was completely blocked by H-89. This indicates that PKA is involved in the activation of the apical Cl(-) channel via c-AMP whereas the shrinkage activation of the Na(+), K(+), 2Cl(-) cotransporter is independent of PKA activation. The steady-state Cl(-) secretion was stimulated by an inhibitor of serine/threonine phosphatases of the PP-1 and PP-2A type and inhibited by a PKC inhibitor but not by a PKA inhibitor. Thus, it seems to be determined by continuous phosphorylation and dephosphorylation involving PKC but not PKA. The steady-state Cl(-) secretion and the maximal obtainable Cl(-) secretion were measured in freshwater-adapted fish and in fish retransferred to saltwater. No I(SC) could be measured in freshwater-adapted fish or in the fish within the first 18 h after transfer to saltwater. As evidenced from Western blot analysis using antiserine-antibodies, a heavily serine phosphorylated protein of about 190 kDa was consistently observed in the saltwater-acclimated fish, but was only weakly present in freshwater-acclimated fish. This observation indicates that acclimatization to saltwater stimulates the expression of this 190-kDa protein and/or a serine/threonine kinase, which subsequently phosphorylates the protein.

Acclimatization↗

Glandular kallikreins in the teleost Cyprinus carpio: tissue distribution, possible involvement in prolactin processing, and effect of 17 beta-estradiol in vivo.

We examined glandular kallikrein (GK), a putative prolactin processing protease, in the teleost Cyprinus carpio. When employing an anti-Centropristis striata GK antibody proteins of 39 kDa in muscle, 52 kDa in gill, 52 kDa in kidney, and two proteins of 46 and 72 kDa in pituitary gland were detected. Immunoreactive kallikreins were recognized in intermuscle cell tissue, epithelial gill cells, apical region of tubular cells, and prolactin producing lactotrophs in pituitary gland, suggesting a osmoregulatory role for this enzyme. We found three prolactin (PRL) variants using anti-tilapia PRL antibodies, in pituitary gland 23 and 16 kDa, and in plasma 23 and 22 kDa forms. Clearly co-localization of GK and PRL in lactotrophs could be demonstrated. In winter-acclimatized male carp, where the pituitary PRL level is low, 17beta-estradiol treatment increased PRL but not GK immunoreactivity. In contrast to GK and PRL co-regulation by estrogen in mammalian pituitary gland, no similar effect on immunoreactive PRL and GK was observed in the ichtyc pituitary. No changes in GK immunostaining occurred in gill or muscle tissue in response to estrogen treatment. These results, taken with the observation of significantly increased GK immunoreactivity in the apical region of kidney tubular cells in estrogen treated male carp, indicate that the regulation of GK expression in pituitary and kidney could be different in fish with respect to mammals.

Acclimatization↗

Influence of alpha-adrenergic blockade on the catecholamine response to exercise at 4,300 meters.

This investigation examined the influence of alpha-adrenergic blockade on plasma and urinary catecholamine responses to both exercise and high-altitude exposure. Sixteen nonsmoking, eumenorrheic women (age 23.2 +/- 1.4 years, 68.7 +/- 1.0 kg) were studied at sea level and during 12 days of high-altitude exposure (4,300 m). Subjects received either alpha-blockade (prazosin 3 mg/d) or a placebo in a double-blinded, randomized fashion. Resting plasma and 24-hour urine samples were collected periodically throughout the duration of the study. Further, subjects participated in submaximal exercise tests (50 minutes at 50% sea level maximum oxygen consumption [Vo2max]) at Sea level and on days 1 and 12 at altitude. Urinary norepinephrine (NE) excretion rates increased significantly over time at altitude, with blocked subjects having greater values compared to controls. Plasma NE levels increased significantly with chronic altitude exposure compared to sea level and acute hypoxia both at rest and during exercise. NE levels at rest were greater for blocked compared to control subjects during all conditions. Urinary and plasma epinephrine (EPI) levels increased dramatically, with acute altitude exposure returning to sea level values by day 12 of altitude exposure. EPI levels were greater for blocked compared to placebo both at rest and during exercise for all conditions studied. Changes in alpha-adrenergic activity over time at altitude were associated with select metabolic and physiologic adjustments. The presence of alpha-blockade significantly affected these responses during chronic altitude exposure. It was concluded that: (1) alpha-adrenergic blockade elicited a potentiated sympathoadrenal response to the stress of both exercise as well as high-altitude exposure, and (2) the sympathetics, via alpha-adrenergic stimulation, contribute to a number of key adaptations associated with acclimatization to high altitude.

Acclimatization↗

Ventilation, EELV and diaphragmatic activity in rats during the early phase of normobaric hypoxia.

We tested whether the enhancement of end-expiratory activity of the diaphragm (DE) induced by acute hypoxia persists during long-lasting hypoxia and participates in the enlargement of end-expiratory lung volume (EELV). We thus measured these two parameters together with ventilation (VE) in 30 rats, either awake or anesthetized, exposed to (1) poikilocapnic hypoxia sustained for 2 or 3 h; or (2) chronic normobaric hypoxia for 7 days interrupted by short episodes of normoxia. Twelve control animals were also studied. (1) Sustained hypoxia induced a stable increase in DE, VE and EELV. (2) In awake rats, chronic hypoxia induced a transient increase in VE after 1 day of hypoxia, and an increase persisting during acute normoxia throughout the exposure. DE followed the same, although less pronounced, course as VE. In anesthetized animals, only EELV was increased in both chronic hypoxia and acute normoxia, but its enlargement in normoxia was not associated with a concomitant increase in DE. The transition from hypoxia to normoxia always induced a decrease in DE and EELV. Therefore, (1) during hypoxia sustained for 2 or 3 h, the ventilatory and diaphragmatic responses were stable; (2) during chronic hypoxia lasting 1 week, a ventilatory acclimatization was expressed by a transient increase in hypoxic VE and a hyperventilation continuing during acute normoxia; (3) EELV enlargement in chronic hypoxia was partly related to changes in DE and partly due to another mechanism possibly involving morphological adaptations.

Acclimatization↗

Ventilation, EELV and diaphragmatic activity in rats during chronic normobaric hypoxia.

We determined the effects of chronic hypoxia on end-expiratory lung volume (EELV), end-expiratory diaphragmatic activity (DE) and ventilation (VE) in 27 intact (awake and anesthetized) and six carotid body-denervated (CBD; anesthetized) rats. Twenty-nine control animals were also studied. Recordings were made during hypoxia and normoxia before and after 2 or 3 weeks of hypoxia (+3 days of recovery from chronic hypoxia). In awake rats, 2 weeks of chronic hypoxia increased only normoxic VE, while 3 weeks of chronic hypoxia did not change VE or DE. In anesthetized intact rats, after both exposures, hypoxic and normoxic VE tended to decrease, DE did not change and hypoxic and normoxic EELV were enlarged. In CBD animals, 2 weeks of chronic hypoxia did not affect hypoxic VE but decreased normoxic ventilation and enlarged EELV similar to the intact animals. After 3 days of recovery in normoxia, all parameters except EELV were restored to prehypoxic values. Also, transition from hypoxia to normoxia induced parallel changes in EELV and DE while chronic hypoxia increased only EELV. Therefore, chronic normobaric hypoxia induced, (1) an increase in normoxic ventilation reflecting a process of acclimatization; (2) an enlargement of EELV that did not depend on changes in DE and carotid chemoreceptors.

Acclimatization↗

Methysergide augments the acute, but not the sustained, hypoxic ventilatory response in goats.

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation that occurs during sustained hypoxia. As serotonin (5-HT) has been reported to be an important modulator of respiratory output, 5-HT may also play a role in VAH. Methysergide (a broad-spectrum 5-HT antagonist), was given to awake goats (1 mg kg(-1) i.v.) 30 min prior to being exposed to 4 h of isocapnic hypoxia. Although methysergide slightly decreased arterial pH, presumably due to a non-significant increase in arterial P(CO2), it did not alter normoxic ventilation. Following methysergide, the expired minute ventilation (VE) was significantly elevated above the control (saline) response after 30 min of hypoxia, but methysergide did not otherwise alter VAH. We repeated the study in the same goats using ketanserin, a specific 5-HT2A/2C receptor antagonist (1.2 mg kg(-1) i.v.). Ketanserin had no effect on the acute hypoxic ventilatory response, or on VAH. We conclude that while 5-HT modulates the acute hypoxic ventilatory response in goats, it does not appear to act through the 5-HT2A/2C receptor subtypes.

Acclimatization↗

Thermoregulatory adaptations associated with training and heat acclimation.

The large metabolic heat load generated as a consequence of muscular work requires activation of thermoregulatory mechanisms in order to prevent an excessive and potentially dangerous rise in body temperature during exercise. Although the horse has highly efficient heat dissipatory mechanisms, there are a number of circumstances in which the thermoregulatory system may be overwhelmed, resulting in the development of critical hyperthermia. The risk for development of life-threatening hyperthermia is greatest when (1) the horse is inadequately conditioned for the required level of physical performance; (2) exercise is undertaken in hot and particularly, in hot and humid ambient conditions; and (3) there is an impairment to thermoregulatory mechanisms (e.g., severe dehydration, anhidrosis). Both exercise training under cool to moderate ambient conditions and a period of repeated exposure to, and exercise in, hot ambient conditions (heat acclimation) will result in a number of physiologic adaptations conferring improved thermoregulatory ability. These adaptations include an expanded plasma volume, greater stability of cardiovascular function during exercise, and an improved efficiency of evaporative heat loss as a result of alterations in the sweating response. Collectively, these adjustments serve to attenuate the rise in core body temperature in response to a given intensity of exercise. The magnitude of the physiologic adaptations occurring during exercise training and heat acclimation is a reflection of the thermal load imposed on the horse. Therefore, when compared with a period of training in cool conditions, the larger thermal stimulus associated with repeated exercise in hot ambient conditions will invoke proportionally greater thermoregulatory adaptations. Although it is not possible to eliminate the effects of adverse environmental conditions on exercise performance, it is clear that a thorough exercise training program together with a subsequent period of acclimatization will serve to ameliorate the impact of the environment. Based on our current understanding of the nature and extent of thermoregulatory adaptations in the horse, the following conclusions can be made: 1. A 2- to 3-month period of exercise training geared toward the specific athletic endeavor to be undertaken will result in substantial improvements in thermoregulatory capacity and is an absolute requirement for horses required to compete in hot ambient conditions. 2. Although physical training in a cool environment improves physiologic responses to exercise at high ambient temperatures, a 2-week period of moderate exercise training in these more adverse conditions is necessary for optimization of thermoregulatory function and physical performance. 3. Heat acclimation does not reduce the need for close monitoring of horses during training and competition in the heat. This is particularly true in hot, humid ambient conditions, where the biophysical limitations to sweat evaporation can result in development of severe hyperthermia, regardless of the state of training or heat acclimation.

Acclimatization↗

High altitude, hypoxic-induced modulation of noradrenergic-mediated responses in fetal and adult cerebral arteries.

In response to high altitude long-term hypoxemia, the cerebral arteries of adult and fetal sheep show decreased contractile responses to norepinephrine and other agonists. In this review, we examine some of the presynaptic and postsynaptic contractile mechanisms that might account for these changes. In addition, we examine cerebral vessel relaxation and the role of pregnancy in altering these responses. In general, high altitude hypoxia is associated with augmented or "upregulation" of presynaptic functions. In contrast, postsynaptic functions tend to be significantly depressed or "downregulated." The results emphasize the role of high altitude, long-term hypoxemia in modulating adrenergic-mediated signal transduction in the cerebral vasculature. They specifically highlight the profound differences in acclimatization responses between common carotid and intracranial arteries, as well as the significant differences between responses in the fetus and adult.

Acclimatization↗

[High altitude and cardiac disease].

Hypoxia at high altitude is associated with an increase in myocardial work. Cardiovascular effects of high altitude may affect patients suffering from cardiac diseases and raise questions concerning the tolerability of exposure to altitude. In general, altitudes up to 2500 to 3000 meters do not pose a hazard for a patient with stable coronary artery disease and good exercise tolerance. Likewise, a patient suffering from heart failure does not necessarily refrain from these altitude exposures unless exercise capacity and left ventricular ejection fraction are severely impaired. However, cardiac patients have to be informed that symptoms may occur already at lesser efforts at high altitude compared to low altitude. Therefore, patients should be advised to adapt physical activities, particularly during the first 3-4 days of acclimatization. In commercial airplanes pressure conditions are comparable to altitudes of 1500 to 2400 meters. Most cardiac patients tolerante the associated physical stress without difficulty. Contraindications for air travel include unstable cardiac conditions, recent cardiac interventions (2-3 weeks), an uncomplicated myocardial infarction within the last 2 weeks, or a complicated myocardial infarction within the last 6 weeks, respectively. The risk of exposure to altitudes above 3500 meters is not well known for cardiac patients because of a lack of corresponding data. Thus, patients who would like to mountaineer at very high altitudes have to be advised individually based on their physical condition and on the severity of their cardiac illness.

Acclimatization↗

Coral reefs: corals' adaptive response to climate change.

The long-term response of coral reefs to climate change depends on the ability of reef-building coral symbioses to adapt or acclimatize to warmer temperatures, but there has been no direct evidence that such a response can occur. Here we show that corals containing unusual algal symbionts that are thermally tolerant and commonly associated with high-temperature environments are much more abundant on reefs that have been severely affected by recent climate change. This adaptive shift in symbiont communities indicates that these devastated reefs could be more resistant to future thermal stress, resulting in significantly longer extinction times for surviving corals than had been previously assumed.

Acclimatization↗

Identifying causal genetic variants for high-altitude adaptation through blood eQTL analysis in plateau populations.

A substantial number of genetic variants have been associated with high-altitude adaptation (HAA), yet most of them are located in non-coding genomic regions, leaving their specific functions and underlying mechanisms largely unknown. In this study, we analyze whole-genome and transcriptome sequencing data from a self-established cohort comprising 61 native highlanders (NHs) and 164 acclimatized newcomers (ANs), identifying 6,586 cis- and 34,203 trans-expression quantitative trait loci (eQTLs), along with 130 cell type-specific eQTLs. By further combining these data with a large East Asia (~30% Tibetan) genome-wide association study (GWAS) cohort, we employ colocalization and causal inference analyses to prioritize 85 cis-eQTLs associated with HAA and identify several novel candidate causal genes, including EXOC8, which is experimentally confirmed to regulate erythroid differentiation. Additionally, network analysis of these causal genes uncovers multiple regulatory pathways, mainly involving energy metabolism, autophagy, ubiquitination and inflammation. Our study offers a comprehensive eQTL map and reveals causal chains of "variant-gene-phenotype" for HAA-related traits, which provides new insights into potential regulatory mechanisms and targets for prevention and treatment of altitude sickness.

Quantitative Trait Loci↗