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Background: Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm., Methods: Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm., Results: Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development., Conclusions: Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb., (Copyright © 2021. Published by Elsevier Ltd.)

Sonographic B-lines can indicate pulmonary interstitial edema. We sought to determine the incidence of subclinical pulmonary edema measured by sonographic B-lines among lowland trekkers ascending to high altitude in the Nepal Himalaya. Twenty healthy trekkers underwent portable sonographic examinations and arterial blood draws during ascent to 5160 m over ten days. B-lines were identified in twelve participants and more frequent at 4240 m and 5160 m compared to lower altitudes (P < 0.03). There was a strong negative correlation between arterial oxygen saturation and the number of B-lines at 5160 m (ρ = -0.75, P = 0.008). Our study contributes to the growing body of literature demonstrating the development of asymptomatic pulmonary edema during ascent to high altitude. Portable lung sonography may have utility in fieldwork contexts such as trekking at altitude, but further research is needed in order to clarify its potential clinical applicability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

High altitude sojourn is broadly associated with impaired cognitive function, although there are inconsistencies within the literature. Incorporation of mathematical modeling to gain insight into latent aspects of decision-making may strengthen the ability to characterize changes in cognitive function during high altitude sojourn. This study sought to examine the effects of high altitude on cognitive function and underlying constructs of decision-making during an 11-d incremental ascent to 5160 m in 18 healthy adults (26 ± 12 yrs). Participants underwent cognitive testing at 116 m, 3440 m, 4240 m, and 5160 m. Cognitive function was assessed using standard metrics of accuracy and reaction time (RT) during working memory (2-back) and attention (Flanker) tasks. Behavioral data were additionally analyzed using drift-diffusion modeling to interrogate latent neural (strength of evidence, non-decision time) and behavioral (caution, bias) processes of decision-making. Flanker accuracy was unaltered during incremental ascent to high altitude, while 2-back accuracy decreased at 5160 m (p < 0.01). RT was faster at 4240 m for the Flanker, and faster at all altitudes compared to 116 m for the 2-back (p < 0.01). Incremental ascent to high altitude elicited modest reductions in caution and non-decision time, increases in bias and strength of evidence for non-match items during the 2-back (0.04 ≥ p > 0.01). These data indicate that while RT may appear to improve during incremental ascent to high altitude, increases in speed may be driven by participants 1) accumulating less evidence before initiating a response (i.e., less cautious) and 2) preferentially attending to (more biased), and extracting more evidence from, frequent/easier stimuli, rather than improved processing per se. Taken together, changes in cognitive function during incremental ascent to high altitude may reflect subtle changes in neural and behavioral components of decision-making intended to reduce cognitive load and conserve brain resources under challenging environmental conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Exercise in hypoxia places added demands on the brain and cerebrovasculature that can impact cognitive function. The purpose of this study was to investigate the effect of acute hypoxia on cerebrovascular hemodynamics, markers of neuro-steroidal modulation and brain-blood barrier (BBB) integrity, and cognition during exercise. Thirty healthy participants (21±4yrs., BMI 24.0±2.6kg∙m(-2); 15 men) were randomized to both a≈2.5h normoxic (FiO2 20.0%) and hypoxic (FiO2 12.5%) condition on two separate days. After 1.25h, participants underwent 10min of exercise-alone (cycling at 55% HRmax) and 15min of exercise+cognitive testing. Prefrontal cortex (PFC) tissue oxygenation and middle cerebral artery (MCA) mean blood velocity (MnV) were measured using near-infrared spectroscopy and transcranial Doppler respectively at rest, during exercise-alone, and during exercise+cognitive testing. Salivary levels of dehydroepiandosterone [DHEA], DHEA-sulfate [DHEAS]) and neuron specific enolase (NSE) were measured pre and post exercise. Cognition was assessed using standard metrics of accuracy and reaction time (RT), and advanced metrics from drift-diffusion modeling across memory recognition, N-Back and Flanker tasks. MCA MnV increased from rest to exercise (p<0.01) and was unchanged with addition of cognitive testing during exercise in both normoxia and hypoxia. PFC oxygenation increased during exercise (p<0.05) and was further increased with addition of cognitive challenge in normoxia but decreased during exercise in hypoxia (p<0.05) with further reductions occurring with addition of cognitive tasks (p<0.05). DHEA and NSE increased and decreased post-exercise, respectively, in both normoxia and hypoxia (p<0.01). Accuracy on cognitive tasks was similar in normoxia compared to hypoxia, while RT was slower in hypoxia vs normoxia across memory recognition (p<0.01) and Flanker tasks (p=0.04). Drift-diffusion modeling suggested changes in memory RT were due to increases in caution (p<0.01). Overall cognitive performance is maintained during exercise in hypoxia concomitant with slower RT in select cognitive tasks and reduced oxygenation in the PFC. These changes were accompanied by slight increases in neuro-steroidal modulation but appear independent of changes in NSE, a biomarker of BBB integrity. Maintained accuracy and select increases in RT during hypoxic exercise may be related behavioral changes in caution., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Highland natives show unique breathing patterns and ventilatory responses at altitude, both at rest and during exercise. For many ventilatory traits, there is also significant variation between highland native groups, including indigenous populations in the Andes and Himalaya, and more recent altitude arrivals in places like Colorado. This review summarizes the literature in this area with some focus on partitioning putative population genetic differences from differences acquired through lifelong exposure to hypoxia. Current studies suggest that Tibetans have high resting ventilation (V (E)), and a high hypoxic ventilatory response (HVR), similar to altitude acclimatized lowlanders. Andeans, in contrast, show low resting V (E) and a low or "blunted" HVR, with little evidence that these traits are acquired via lifelong exposure. Resting V (E) of non-indigenous altitude natives is not well documented, but lifelong hypoxic exposure almost certainly blunts HVR in these groups through decreased chemosensitivity to hypoxia in a process known as hypoxic desensitization (HD). Together, these studies suggest that the time course of ventilatory response, and in particular the origin or absence of HD, depends on population genetic background i.e., the allele or haplotype frequencies that characterize a particular population. During exercise, altitude natives have lower V (E) compared to acclimatized lowland controls. Altitude natives also have smaller alveolar-arterial partial pressure differences P(AO2) - P(aO2) during exercise suggesting differences in gas exchange efficiency. Small P(AO2) - P(aO2) in highland natives of Colorado underscores the likely importance of developmental adaptation to hypoxia affecting structural/functional aspects of gas exchange with resultant changes in breathing pattern. However, in Andeans, at least, there is also evidence that low exercise V (E) is determined by genetic background affecting ventilatory control independent of gas exchange. Additional studies are needed to elucidate the effects of gene, environment, and gene-environment interaction on these traits, and these effects are likely to differ widely between altitude native populations.

Variation in human athletic performance is determined by a complex interaction of socio-cultural, psychological, and proximate physiological factors. Human physiological trait variance has both an environmental and genetic basis, although the classic gene-environment dichotomy is clearly too simplistic to understand the full range of variation for most proximate determinants of athletic performance, e.g., body composition. In other words, gene and environment interact, not just over the short term, but also over the lifetime of an individual with permanent effects on the adult phenotype. To further complicate matters, gene and environment may also be correlated. That is, genetically gifted individuals may be identified as children and begin training pulmonary, cardiovascular, and muscle systems at an early critical age. This review covers evidence in support of a genetic basis to human athletic performance, with some emphasis on the recent explosion of candidate gene studies. In addition, the review covers environmental influences on athletic performance with an emphasis on irreversible environmental effects, i.e., developmental effects that may accrue during critical periods of development either before conception (epigenetic effects), during fetal life (fetal programming), or during childhood and adolescence. Throughout, we emphasize the importance of gene-environment interaction (G x E) as a means of understanding variation in human physiological performance and we promote studies that integrate genomics with developmental biology.

To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothelial growth factor (VEGF) expression in response to exercise or hypoxia, rats underwent 1h sciatic nerve electrical stimulation (ES), hypoxic exposure (H) or combined stimuli. HIF-1alpha protein levels increased six-fold with maximal (8V) ES with or without H. Similar HIF-1alpha increases occurred with sub-maximal (6V and 4V) ES plus H, but not in sub-maximal ES or H alone. VEGF mRNA and protein levels increased three-fold in sub-maximal ES or H alone, six-fold in sub-maximal ES plus H, 6.3-fold with maximal ES, and 6.5-fold after maximal ES plus H. These data suggest: (1) intracellular hypoxia during normoxic exercise may exceed that during 8% oxygen breathing at rest and is more effective in stimulating HIF-1alpha; (2) HIF-1 may be an important regulator of exercise-induced VEGF transcription; and (3) breathing 8% O(2) does not alter HIF-1alpha expression in skeletal muscle, implying that exercise-generated signals contribute to the regulation of HIF-1alpha and/or VEGF.