Sex disparities in the association between rare earth elements
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2025-01-21
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Sex disparities in the association between rare earth elements exposure and genetic mutation frequencies in lung cancer patients
source:Scientific ReportsThe ubiquitous use of rare earth elements (REEs) in modern living environments raised concern about their impact on human health. With the detrimental and beneficial effects of REEs reported by different studies, the genuine role of REEs in the human body remains a mystery. This study explored the association between REEs and genetic mutations in patients with lung adenocarcinoma (LUAD). A cohort of 53 LUAD patients underwent tumor DNA sequencing (1123 cancer-related genes) and plasma REE (lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), and yttrium (Y)) quantification. We found divergent relationships between plasma REE levels and mutation load between sexes. Specifically, Ce levels and mutation load were positively correlated in males but negatively correlated in females, while La exposure exhibited opposite associations in the two sexes. This observation was validated using the Bayesian Kernel Machine Regression (BKMR) model. Additionally, plasma REE levels was associated with specific mutation types and variant allele frequencies (VAFs) of particular genes in a sex-dependent manner. Mutational signature analysis revealed sex-specific associations of La with indel signatures. These findings highlight the intricate interplay between plasma REE levels and genetic mutations in LUAD, emphasizing the need for a personalized, sex-oriented approach to understand and treat this disease.The rare earth elements (REEs) consist of 14 lanthanides, as well as scandium and yttrium, which exhibit similar chemical properties to lanthanides. The widespread applications of REEs in industrial, agricultural, and iatrogenic technologies have raised concern about their impact on human health, as reflected by the growing literature on REE-related adverse effects1. To our knowledge, no essential biological function of these elements and their compounds has been established. A body of experimental studies have suggested that high level of REE exposure exerts a damaging effect on multiple in vivo or in vitro models2,3,4,5,6. However, the exact biological impact of REEs is still an unsolved controversy. The beneficial effects of REEs have been documented in many studies, as the REEs have been supplemented in fertilizers in agriculture practice to improve plant health and used as feed additives in veterinary to boost animal production7,8. Thus, the exact function of REEs in organic systems needs to be further elucidated.Epidemiological studies on the association between REEs and diseases have increased in recent years. The high exposure levels of REEs have been related to the risk of disrupted fetal development9,10. For housewives in Shanxi province of China, higher concentrations of hair REEs were associated with hypertension11. The application of Gd as a contrast agent in iatrogenic practice can cause severe damage to brain tissue and give rise to nephrogenic systemic fibrosis12. However, on the other end, studies on human population also documented the beneficial effects of REEs. Higher levels of serum REEs during early pregnancy were related to a decreased risk of gestational diabetes mellitus13. A recent study demonstrated that prenatal exposure to REEs was positively associated with the telomere length of newborn cord blood14. Moreover, Ce has been reported to act as an antioxidant to scavenge ROS at physiological pH and as a pro-oxidant to generate ROS under low pH environments in cancer cells15. In concordance with this finding, Ce concentration was linked with a lower risk for oral cancer in a recent study16. Another study showed a U-shaped relationship between serum La levels and oral cancer risk, suggesting a protective role of La under low concentrations17.The etiology of cancer is highly complex, and the genetic mutations that lead to activation oncogenes or suppression of cancer suppressor genes have long been considered a major contributor to carcinogenesis. In recent years, progressions in high-throughput DNA sequencing techniques have dramatically broadened our knowledge about cancer occurrence and development mechanisms from the molecular perspectives. However, the link between REE exposure and genomic variation is still a knowledge gap in the current field of cancer research.Lung cancer has been regarded as a distinct disease in women related to that in men. Besides the distinct environmental exposures that are imposed as different risk factors for lung cancer, sexual hormones such as estrogen, testosterone, and androgen could also related to lung cancer development in different sexes18,19. The expression of the estrogen receptor was reported to be elevated in many lung cancers, and the use of hormonal therapy was associated with a decreased risk for lung cancer in non-smoking women20. REEs have been known to promote growth in animals through their influence on hormone secretion, especially the hypothalamic-pituitary-thyroid axis21,22, which is tightly related to the hypothalamic-pituitary-gonadal axis23. A high dose of Ce exposure in mice could directly result in reduced serum concentration of testosterone24. Although the mechanism of how REEs influence the sexual hormone system remains unclear, studies have identified different accumulation and health impacts of REEs between the two sexes22,25,26. Based on the best of our knowledge, no previous study has reported the implication of REE in genetic mutations among lung cancer patients or even the sex-based disparities in this carcinogenic process.La, Ce, and Y constitute roughly 63% of the overall exposure of the 16 REEs27, and La, Ce, Pr, Nd, and Y are the most abundant REEs in the street dust of central China28. In this study, we aspired to investigate the association between these five lanthanides and genetic mutation in cancer patients, shedding light on the impact of REE exposure on the genome stability involved in cancer development. A large next-generation sequencing (NGS) panel (consisting of 1123 cancer-related genes) was utilized to detect gene mutations. Meanwhile, we adopted the plasma REE concentration as a proxy for whole-body REE exposure level. The plasma concentrations of La, Ce, Pr, Nd, and Y were assessed using inductively coupled plasma mass spectrometry (ICP-MS). Applying the Bayesian kernel machine regression (BKMR) model, we found a negative association between the joint exposure level of these REEs and the frequencies of genetic variations.
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