High-altitude hypoxia reduces male semen quality via regulating metabolic pathways: a combined cross-sectional and metabolomic study

China possesses a vast high-altitude territory, and migrant males with long-term plateau residency face reproductive health risks manifested as hypoxia-induced deterioration of semen quality, which constitutes a key public health challenge requiring targeted prevention and control in high-altitude regions. Addressing this public health scientific issue, this study compares semen parameters and plasma metabolomic profiles between adult males residing at plateau and plain altitudes, aiming to elucidate the molecular mechanisms by which hypoxia regulates metabolic pathways to impair semen quality, screen potential biomarkers for reproductive damage in high-altitude males, and provide population-based epidemiological evidence for health authorities to formulate reproductive health protection policies for migrant populations living in plateau areas.

A cross-sectional study was conducted. Healthy male volunteers were recruited from high-altitude regions (Xinjiang, altitude 4000 m) and plain regions (Jiangsu, altitude <500 m) between June and November 2025. The plain group (Group P) included 29 healthy males, and the high-altitude group (Group G, non-indigenous healthy males residing at high altitude for ≥6 months) included 61 males. Semen samples were collected at 3 to 7 d after abstinence, and computer-aided sperm analysis (CASA) was applied to detect semen volume, sperm concentration, progressive motility, and total sperm motility. Stratified random sampling was used to select 20 males from Group P and 54 males from Group G, yielding 74 plasma samples for untargeted metabolomic detection by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).

① In terms of baseline characteristics and semen quality, the Group G showed significantly younger age, and lower BMI, semen volume, sperm concentration, progressive motility, and total sperm motility, while longer abstinence duration compared with the plain group (P<0.05). After adjusting for confounding factors including age, BMI, and abstinence duration, multivariate linear regression analysis revealed that altitude was an independent risk factor for semen volume, sperm concentration, progressive motility, and total sperm motility. ② A total of 291 differential metabolites were identified by plasma metabolomics, of which 173 were upregulated and 118 were downregulated in the Group G. Pathway enrichment analysis indicated that diverse environmental microbial metabolism, phenylalanine metabolism, and GABAergic synapse pathways were positively enriched in the Group G, whereas arachidonic acid metabolism, vitamin digestion and absorption, and fat digestion and absorption pathways were negatively enriched. ③ Correlation analysis showed that the upregulated metabolites including p-toluic acid, styrene, D-fructose-1, 6-bisphosphate, and 2-phenylethanol were negatively correlated with sperm motility (P<0.05), while downregulated metabolites including arachidonic acid, leukotriene B₄, and various lysophosphatidic acid subtypes [LPA 18∶1, LPA 18∶2, LPA(0∶0/18∶2 (9Z, 12Z))] were positively correlated with sperm concentration and motility (P<0.05).

High-altitude hypoxia independently reduces semen quality, and the underlying mechanism is associated with abnormal activation of intestinal microbial metabolism and phenylalanine metabolism pathways, as well as inhibition of arachidonic acid and lipid absorption pathways. The above characteristic differential metabolites may serve as potential early warning targets for reproductive damage in plateau males.

For national and provincial health commissions, male reproductive health of plateau migrants should be incorporated into routine plateau public health monitoring system. Simple screening indicators should be developed based on metabolites identified in this study. Standardized reproductive health physical examinations should be implemented for personnel before and during plateau residence. Targeted dietary guidance supplemented with polyunsaturated fatty acids and anti-oxidants should be promoted for plateau populations.