Doctoral Dissertation Improvement: Physiological Adaptation to Pregnancy at High Altitude: A Comparative Study

在高海拔地区（2500米或8000英尺），大气（气压）的重量减少，氧气供应减少。 这种氧气供应减少或缺氧导致婴儿在子宫内生长缓慢，出生时体重减轻。 由于出生时身材矮小的婴儿在婴儿期和以后的生活中死亡的风险增加，高海拔的这种影响通常被认为是适应不良的。 相对于新来的群体，具有多代高海拔祖先的婴儿受到保护，免受这种有害影响，这表明这种长期群体更好地适应。 由于妊娠结局影响三个个体（母亲，父亲和婴儿）的生殖健康，因此妊娠是生命周期中合理且可能敏感的一部分，在此期间可以检查选择性过程。 目前还不清楚是什么原因使得这些长期妊娠的胎儿比新生儿缺氧相关的宫内生长受限（IUGR）的影响更小。 此外，尽管我们知道基因影响胎儿的生长和母体对妊娠并发症（如先兆子痫）的易感性，但所涉及的特定基因或它们发挥作用的生理过程还不清楚。在这项研究中，我们假设多代高海拔居民经历了遗传变异的自然选择，这些遗传变异有助于增强母体的抗氧化能力或减少氧化应激。 支持这一假设的是以前的研究表明，1）氧化应激有助于受损的母体血管功能的先兆子痫和IUGR在低海拔地区; 2）居住在高海拔地区减少母体子宫动脉血流量和氧气输送到婴儿;和3）几种抗氧化酶的活性是更大的高原人群比低地血统。 然而，尚不清楚高海拔地区妊娠期间氧化应激的增加是否会导致观察到的先兆子痫和IUGR的发生率更高，或者与低地血统相比，高原女性是否能够通过产生更少的氧化应激源或更多的抗氧化剂来更好地保护自己免受氧化应激的影响。设计图：我们将比较氧化应激，抗氧化状态和母体血管适应怀孕，胎儿生长的生理措施，在怀孕/胎儿生活的安第斯山脉或欧洲血统的人谁住在低（300米）或高（3600米）海拔玻利维亚。 玻利维亚拥有西半球最多的高地人口。这种设计能够识别母体对高海拔妊娠的表型反应与胎儿生长之间的时间关系，并将为潜在的适应性途径提供信息。更广泛的影响：玻利维亚的产妇死亡率是拉丁美洲的两倍，婴儿死亡率是西半球最高的。 更好地了解孕产妇/婴儿健康的遗传、生理、社会经济和文化决定因素，将有助于采取更有针对性的干预措施。 玻利维亚的医生和工作人员将帮助开展这项研究，为在机会有限的国家发展研究技能提供机会。 研究成果将通过会议报告、期刊文章、公开演讲以及人类学、生理学和公共卫生方面的大学课程进行传播。

The decreased weight of the atmosphere (barometric pressure) at high altitudes (2500m or 8000 ft) reduces oxygen availability. Such reduced oxygen availability or hypoxia causes babies to grow more slowly while in the womb and weigh less at birth. Because babies who are born small have an increased risk of dying during infancy as well as later in life, such effects of high altitude are generally considered maladaptive. Babies with multiple generations of high-altitude ancestry are protected relative to newcomer groups from such harmful effects, suggesting that such long-term groups are better adapted. Since pregnancy outcome influences the reproductive fitness of three individuals (mother, father and baby), pregnancy is a logical, and likely sensitive, portion of the lifecycle during which to examine selective processes. Unknown is what permits such long-term groups to be less affected than newcomers from hypoxia-associated intrauterine growth restriction (IUGR). Moreover, even though we know that genes influence fetal growth and maternal susceptibility to pregnancy complications such as preeclampsia, the particular genes involved or the physiological processes through which they exert their effects are not well understood.In this research, we hypothesize that multigenerational high-altitude residents have undergone natural selection for genetic variants that serve to enhance maternal antioxidant capacity or reduce oxidative stress. Supporting this hypothesis are previous studies showing that 1) oxidative stress contributes to impaired maternal vascular function of preeclampsia and IUGR at low altitude; 2) residence at high altitude decreases maternal uterine artery blood flow and oxygen delivery to the baby; and 3) the activity of several antioxidative enzymes is greater in populations of highland than lowland ancestry. Unknown, however, is whether increased oxidative stress during pregnancy at high altitude contributes to the higher rates of preeclampsia and IUGR observed, or whether women of highland compared with lowland ancestry are better able to defend themselves against oxidative stress by producing fewer oxidative stressors or more antioxidants. Design: We will compare physiological measures of oxidative stress, antioxidant status, and maternal vascular adaptation to pregnancy, and fetal growth across pregnancy/fetal life persons of Andean or European ancestry who live at low (300m) or high (3600m) altitude in Bolivia. Bolivia houses the largest highland population in the Western Hemisphere. This design enables the identification of temporal relationships between maternal phenotypic responses to high-altitude pregnancy and fetal growth, and will be informative of potential adaptive pathways. Broader impacts: Maternal mortality rates in Bolivia are twice that of Latin America and its infant mortality is the highest in the Western Hemisphere. Better understanding of the genetic, physiological, socioeconomic and cultural determinants of maternal/infant health will enable better-targeted interventions. Bolivian physicians and staff will help conduct of this study, providing an opportunity to develop research skills in a country where such opportunities are limited. Study outcomes will be disseminated via conference presentations, journal articles, public talks, and university curricula in anthropology, physiology and public health.