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Int J Mol Sci. 2020 Jan 16;21(2). pii: E582. doi: 10.3390/ijms21020582.

Influence of Sex on Urinary Organic Acids: A Cross-Sectional Study in Children.

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Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', 80131 Napoli, Italy.
CEINGE-Biotecnologie Avanzate Scarl, 80145 Naples, Italy.
Department of Mental and Physical Health, Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy.
Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, 07100 Sassari, Italy.
Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.


The characterization of urinary metabolome, which provides a fingerprint for each individual, is an important step to reach personalized medicine. It is influenced by exogenous and endogenous factors; among them, we investigated sex influences on 72 organic acids measured through GC-MS analysis in the urine of 291 children (152 males; 139 females) aging 1-36 months and stratified in four groups of age. Among the 72 urinary metabolites, in all age groups, 4-hydroxy-butirate and homogentisate are found only in males, whereas 3-hydroxy-dodecanoate, methylcitrate, and phenylacetate are found only in females. Sex differences are still present after age stratification being more numerous during the first 6 months of life. The most relevant sex differences involve the mitochondria homeostasis. In females, citrate cycle, glyoxylate and dicarboxylate metabolism, alanine, aspartate, glutamate, and butanoate metabolism had the highest impact. In males, urinary organic acids were involved in phenylalanine metabolism, citrate cycle, alanine, aspartate and glutamate metabolism, butanoate metabolism, and glyoxylate and dicarboxylate metabolism. In addition, age specifically affected metabolic pathways, the phenylalanine metabolism pathway being affected by age only in males. Relevantly, the age-influenced ranking of metabolic pathways varied in the two sexes. In conclusion, sex deeply influences both quantitatively and qualitatively urinary organic acids levels, the effect of sex being age dependent. Importantly, the sex effects depend on the single organic acid; thus, in some cases the urinary organic acid reference values should be stratified according the sex and age.


GC; mass spectrometry; sex-specific reference values; urine metabolome

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