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

Abstract

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.

The Urinary Metabolome of Healthy Newborns

“…In addition, glucose and lactose were also found to be higher in females, but infant females also had lower levels of inositols and other sugars, suggesting that changes in sugar metabolism may be associated with gender in the first days of life [37]. More recently, Caterino et al [36] analyzed urinary organic acids in healthy Caucasian infants and children (aged 1 month to 36 months), and reported that in the first six months of life, sex differences were more frequent, and the majority of urinary organic acids were higher in males than in females. The authors conclude that sex deeply influences urinary organic acids levels [36].…”

“…It is commonly understood that sex differences start in utero [35] and the implementation of sex or gender-dependent strategies in laboratory medicine may help to obtain the correct diagnosis of diseases affecting newborns. Only a handful of studies have been published addressing the effect of gender in the urinary newborn metabolome [30,36,37]. In particular, Diaz et al [37] reported that allantoin and xanthine levels are higher in the urine of females than in males, which suggests a slightly altered nitrogen metabolism in females, compared to males.…”

“…More recently, Caterino et al [36] analyzed urinary organic acids in healthy Caucasian infants and children (aged 1 month to 36 months), and reported that in the first six months of life, sex differences were more frequent, and the majority of urinary organic acids were higher in males than in females. The authors conclude that sex deeply influences urinary organic acids levels [36]. In our study, we only found significant sex differences in the level of two organic acids: uric acid and butyric acid (higher in males than in females).…”

Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

“…Protein lysates from cells were obtained upon lysis in a RIPA buffer (Sigma-Aldrich, St. Louis, MO, USA) and centrifugation at 14,000× g for 30 min at 4 • C to collect the protein supernatant. For urine proteins, urine samples were collected as described [51] and concentrated using centrifugal filters Amicon Ultra-15 3k (Millipore, Burlington, MA, USA). Protein extracts were fractionated by a 10% SDS-PAGE, and transferred onto nitrocellulose membranes using a Trans-Blot Turbo Transfer System (Bio-Rad, Hercules, CA, USA).…”

Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism

“…Multivariate statistical analysis and metabolite set enrichment analysis were performed using MetaboAnalyst 4.0 ( ) [ 75 ]. The normalized metabolic dataset was log(2)-transformed and scaled according to the Pareto scaling method.…”