Metabolic Profiling Analysis of Congenital Adrenal Hyperplasia via an
                    Untargeted Metabolomics Strategy

Fangling Liu; Chongxin Kang; Zheng Hu; Xiaoping Luo; Wei Wu; Qiuying Tao; Quan Chi; Jing Yang; Xian Wang

doi:10.1055/a-2365-7521

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2025; 57(01): 39-46
DOI: 10.1055/a-2365-7521

Original Article: Endocrine Care

Metabolic Profiling Analysis of Congenital Adrenal Hyperplasia via an Untargeted Metabolomics Strategy

Fangling Liu

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

,

Chongxin Kang

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

,

Zheng Hu

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

,

Xiaoping Luo

²Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

,

Wei Wu

²Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

,

Qiuying Tao

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

,

Quan Chi

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

,

Jing Yang

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

,

Xian Wang

¹Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan, China (Ringgold ID: RIN12404)

› Institutsangaben

Abstract

Congenital adrenal hyperplasia (CAH) manifests as an autosomal recessive disorder characterized by defects in the enzymes responsible for steroid synthesis. This work aims to perform metabolic profiling of patients with CAH, screen key differential metabolites compared to the control group, and discover the associated metabolic pathways implicated in CAH. Serum samples obtained from 32 pediatric male patients with CAH and 31 healthy control group candidates were subjected to analysis using non-targeted metabolomics strategy using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 278 differential metabolites were identified and annotated in KEGG. Operating characteristic curves (ROC) measurement exhibited 9 metabolites exhibiting high efficacy in differential diagnosis, as evidenced by an area under ROC curve (AUC) exceeding 0.85. Pathway analysis uncovered notable disruptions in steroid hormone biosynthesis (p <0.0001), purine metabolism and irregularities in lipid metabolism and amino acid metabolism, including tyrosine and alanine, in CAH patients. These findings demonstrate that metabolic pathways of purine, amino acid and lipid metabolism, apart from steroid hormone biosynthesis, may be disrupted and associated with CAH. This study helps provide insight into the metabolic profile of CAH patients and offers a new perspective for monitoring and administering follow-up care to CAH patients.

Keywords

congenital adrenal hyperplasia - untargeted metabolomics - differential metabolites - metabolic pathways - ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)

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References
1 El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet 2017; 390: 2194-2210
2 Lu W, Zhang T, Zhang L. et al. Clinical characteristics of a male child with non-classic lipoid congenital adrenal hyperplasia and literature review. Front Endocrinol 2022; 13: 947762
3 Engels M, Gehrmann K, Falhammar H. et al. Gonadal function in adult male patients with congenital adrenal hyperplasia. Eur J Endocrinol 2018; 178: 285-294
4 Hamed SA, Metwalley KA, Farghaly HS. Cognitive function in children with classic congenital adrenal hyperplasia. Eur J Pediatr 2018; 177: 1633-1640
5 Speiser PW, Arlt W, Auchus RJ. et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol 2018; 103: 4043-4088
6 Odom JD, Sutton VR. Metabolomics in clinical practice: improving diagnosis and informing management. Clin Chem 2021; 67: 1606-1617
7 Cui L, Lu HT, Lee YH. Challenges and emergent solutions for LC-MS/MS based untargeted metabolomics in diseases. Mass Spectrom Rev 2018; 37: 772-792
8 Gertsman I, Barshop BA. Promises and pitfalls of untargeted metabolomics. J Inherit Metab Dis 2018; 41: 355-366
9 Gagnebin Y, Julien B, Belén P. et al. Metabolomics in chronic kidney disease: Strategies for extended metabolome coverage. J Pharmaceut Biomed Anal 2018; 161: 313-325
10 Alwashih MA, Watson DG, Andrew R. et al. Plasma metabolomic profile varies with glucocorticoid dose in patients with congenital adrenal hyperplasia. Sci Rep 2017; 7: 17092
11 Claahsen van der Grinten HL, Speiser PW, Ahmed SF. et al. Congenital adrenal hyperplasia - current insights in pathophysiology, diagnostics and management. Endocr Rev 2021; 43: 91-159
12 Navardauskaite R, Semeniene K, Sukys M. et al. Cardiometabolic health in adolescents and young adults with congenital adrenal hyperplasia. Medicina 2022; 58: 500
13 Kamrath C, Hartmann MF, Pons-Kühnemann J. et al. Urinary GC–MS steroid metabotyping in treated children with congenital adrenal hyperplasia. Metabolism 2020; 112: 154354
14 Nguyen LS, Prifti E, Ichou F. et al. Effect of congenital adrenal hyperplasia treated by glucocorticoids on plasma metabolome: a machine-learning-based analysis. Sci Rep 2020; 10: 8859
15 Georgiev KD, Radeva-Ilieva M, Stoeva S. et al. Isolation, analysis and in vitro assessment of CYP3A4 inhibition by methylxanthines extracted from Pu-erh and Bancha tea leaves. Sci Rep 2019; 9: 13941
16 Vrzal R, Stejskalova L, Monostory K. et al. Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact 2008; 179: 288-296
17 Soo JY, Wiese MD, Dyson RM. et al. Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs. Plos One 2020; 15: e0233010
18 Satoh N, Nakamura M, Suzuki A. et al. Effects of nitric oxide on renal proximal tubular Na⁺ transport. BioMed Res Int 2017; 6871081
19 Lin Y, Yang Z, Li J. et al. Effects of glutamate and aspartate on prostate cancer and breast cancer: a Mendelian randomization study. BMC Genomics 2022; 23: 1-12
20 Li B, Wang J, Liao J. et al. YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration. Cancer Cell Int 2022; 22: 287
21 Holeček M. Roles of malate and aspartate in gluconeogenesis in various physiological and pathological states. Metabolism 2023; 145: 155614
22 Harrison SA, Webb WL, Rammu H. et al. Prebiotic synthesis of aspartate using life’s metabolism as a guide. Life 2023; 13: 1177
23 Rumping L, Vringer E, Houwen RHJ. et al. Inborn errors of enzymes in glutamate metabolism. J Inherit Metab Dis 2019; 43: 200-215
24 Qi M, Wang J, Tan BE. et al. Dietary glutamine, glutamate, and aspartate supplementation improves hepatic lipid metabolism in post-weaning piglets. Anim Nutr 2020; 6: 124-129
25 Jin J, Byun J-K, Choi Y-K. et al. Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp Mol Med 2023; 55: 706-715
26 Bai L, Bernard K, Tang X. et al. Glutaminolysis epigenetically regulates antiapoptotic gene expression in idiopathic pulmonary fibrosis fibroblasts. Am J Respir Cell Mol Biol 2019; 60: 49-57
27 Jankowska-Kulawy A, Klimaszewska-Łata J, Gul-Hinc S. et al. Metabolic and cellular compartments of acetyl-CoA in the healthy and diseased brain. Int J Mol Sci 2022; 23: 10073
28 Ying M, Guo C, Hu X. The quantitative relationship between isotopic and net contributions of lactate and glucose to the tricarboxylic acid (TCA) cycle. J Biol Chem 2019; 294: 9615-9630
29 Manso G, Baker AJ, Taylor IK. et al. In vivo and in vitro effects of glucocorticosteroids on arachidonic acid metabolism and monocyte function in nonasthmatic humans. Eur Respir J 1992; 5: 712-716
30 de Kloet AD, Herman JP. Fat-brain connections: Adipocyte glucocorticoid control of stress and metabolism. Front Neuroendocrin 2018; 48: 50-57
31 Kuo T, Chen T-C, Lee RA. et al. Pik3r1 is required for glucocorticoid-induced perilipin 1 phosphorylation in lipid droplet for adipocyte lipolysis. Diabetes 2017; 66: 1601-1610
32 Stimson RH, Anderson AJ, Ramage LE. et al. Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct. Diabetes Obes Metab 2017; 19: 883-891
33 Ren X, Shao Z, Fan W. et al. Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits. J. Orthop Surg Res 2020; 15: 1-14
34 Poggiogalle E, Jamshed H, Peterson CM. Circadian regulation of glucose, lipid, and energy metabolism in humans. Metabolism 2018; 84: 11-27

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