The sweat metabolome of screen-positive cystic fibrosis infants: revealing mechanisms beyond impaired chloride transport

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dc.creatorAdriana Nori de Macedo
dc.creatorStellena Mathiaparanam
dc.creatorLauren Brick
dc.creatorKatherine Keenan
dc.creatorTanja Gonska
dc.creatorLinda Pedder
dc.creatorStephen Hill
dc.creatorPhilip Britz-Mckibbin
dc.date.accessioned2022-11-09T19:41:30Z
dc.date.accessioned2025-09-08T23:49:38Z
dc.date.available2022-11-09T19:41:30Z
dc.date.issued2017
dc.identifier.doihttps://doi.org/10.1021/acscentsci.7b00299
dc.identifier.issn2374-7943
dc.identifier.urihttps://hdl.handle.net/1843/47093
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofACS Central Science
dc.rightsAcesso Restrito
dc.subjectQuímica analítica
dc.subjectAnions
dc.subjectGenética
dc.subjectMetabolismo
dc.subjectMonômeros
dc.subjectPeptídios
dc.subjectProteínas
dc.subjectEletroforese capilar
dc.subjectEspectrometria de massa
dc.subjectGlândulas sudoríparas
dc.subjectFibrose cística
dc.subject.otherCystic fibrosis
dc.subject.otherMetabolomics
dc.subject.otherSweat
dc.subject.otherCapillary electrophoresis
dc.subject.otherMass spectrometry
dc.subject.otherEspectrometria de massa
dc.titleThe sweat metabolome of screen-positive cystic fibrosis infants: revealing mechanisms beyond impaired chloride transport
dc.typeArtigo de periódico
local.citation.epage913
local.citation.issue8
local.citation.spage904
local.citation.volume3
local.description.resumoThe sweat chloride test remains the gold standard for confirmatory diagnosis of cystic fibrosis (CF) in support of universal newborn screening programs. However, it provides ambiguous results for intermediate sweat chloride cases while not reflecting disease progression when classifying the complex CF disease spectrum given the pleiotropic effects of gene modifiers and environment. Herein we report the first characterization of the sweat metabolome from screen-positive CF infants and identify metabolites associated with disease status that complement sweat chloride testing. Pilocarpine-stimulated sweat specimens were collected independently from two CF clinics, including 50 unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted metabolite profiling was performed using multisegment injection–capillary electrophoresis–mass spectrometry as a high throughput platform for analysis of polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic acids, amino acid derivatives, dipeptides, purine derivatives, and unknown exogenous compounds were identified in sweat when using high resolution tandem mass spectrometry, including metabolites associated with affected yet asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid, and a plasticizer metabolite from environmental exposure, mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at significantly lower concentrations relative to unaffected CF screen-positive controls. These results indicated a deficiency in human paraoxonase, an enzyme unrelated to mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) and impaired chloride transport, which is a nonspecific arylesterase/lactonase known to mediate inflammation, bacterial biofilm formation, and recurrent lung infections in affected CF children later in life. This work sheds new light into the underlying mechanisms of CF pathophysiology as required for new advances in precision medicine of orphan diseases that benefit from early detection and intervention, including new molecular targets for therapeutic intervention.
local.identifier.orcidhttps://orcid.org/0000-0002-4125-3755
local.identifier.orcidhttps://orcid.org/0000-0001-8524-6314
local.identifier.orcidhttps://orcid.org/0000-0001-5586-0284
local.identifier.orcidhttps://orcid.org/0000-0001-6786-4354
local.identifier.orcidhttps://orcid.org/0000-0002-6055-0771
local.identifier.orcidhttps://orcid.org/0000-0001-9296-3223
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://pubs.acs.org/doi/full/10.1021/acscentsci.7b00299

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