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Metabonomics approach detects fetal abnormalities
HAF samples were obtained from pregnant women who had undergone amniocentesis for cytogenetic testing; 51 control samples were from healthy fetuses and 12 samples were from fetuses diagnosed with malformations in various tissues. When HAF samples were analyzed by 1H NMR, the standard 1D spectra showed many overlapping broad and narrow peaks that were often difficult to
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cant differences in HAF composition between control and malformed fetuses. Amniocentesis, a procedure in which a Although the 12 fetuses had been diagsmall amount of human amniotic fluid nosed with distinct types of malforma(HAF) is extracted from the sac that surtion (e.g., cardiac, central nervous sysrounds a fetus, has revolutionized the tem, or abdominal), most shared a prenatal diagnosis of disease. But the common set of metabolite variations ∼2-week wait to obtain results from gethat suggested kidney underdevelopment netic and biochemical testing of HAF and the hypoxia-induced enhancement can be nerve-wracking, especially for of glycolysis and gluconeogenesis. “Eiwomen with worrisome ther as a cause or a conseultrasonography or blood quence of fetal malformatest findings or a family tions, some metabolic history of birth defects. Bepathways and organs are cause faster and more reliaffected, in addition to the able methods to diagnose physically malformed feafetal malformations are tures,” says Gil. needed, Ana M. Gil and According to John Lindon colleagues at the University at Imperial College London, of Aveiro, the University of “There have been only a few Coimbra, and Centro Hossmall studies on amniotic pitalar de Coimbra (all in fluid to date, and thus this Portugal) compared mestudy represents an importabolites in HAF from contant advance in investigating trol and malformed fetuses the fluid and the use of by using 1H-NMR spectrosNMR-based metabonomics as a screening and diagnostic copy. They report their retool.” However, because of sults in a new JPR paper Judging fetal health. In a new study, metabolite levels measured in human amniotic fluid by using 1H-NMR spectroscopy were shown to correlate with the small sample size and (DOI 10.1021/pr900386f). fetal malformations. heterogeneous malformation “The initial motivation to types, “much more work and start this project was the validation would be needed realizationsactually by perinterpret. To simplify analysis, the rebefore the method could reach the clinic.” sonal experiencesthat the genetic and searchers collected two other types of 1D Ian Colquhoun of the Institute of Food biochemical tests performed on HAF give spectra for each sample: Carr-PurcellResearch (U.K.) says that because NMR results only after a few weeks, which is a Meiboom-Gill (CPMG) and diffusiondetects primarily high-concentration comperiod too long to endure, especially if edited spectra, which show mainly sigpounds, “[Gil’s] data are more likely to be there is cause for worry,” says Gil. “That nals from small and large compounds, useful for the light they throw on fetal biowait surely causes stress to the pregnant respectively. (The researchers also colchemistry and metabolism than as a powoman and demonstrates a need for fastlected 2D spectra to help assign the tential diagnostic tool. The use of more response analytical methods.” Prenatal peaks.) sensitive MS-based metabolomics methdiagnostic methods also suffer from occaThe key to revealing differences in ods might uncover better diagnostic sional false results and ambiguities, and HAF composition between control and marker compounds.” some pregnancy-related disorders lack malformed fetuses was an advanced Gil plans to validate the HAF data with predictive tools. statistical tool called orthogonal partial more samples as they become available Therefore, Gil and co-workers used 1H least squares discriminant analysis and with complementary methods such as NMR to detect differences in the metabo(OPLS-DA). According to Gil, “OPLSMS, and she wants to explore the metabolite composition of HAF from control and DA detects only metabolites that vary lite compositions of other biofluids from malformed fetuses at 15-24 weeks gestaconsistently in the same direction in pregnant women. “The fact that there are tion (the recommended period for amniomost or all malformation samples metabolic differences between the HAF of centesis in Portugal). “NMR has a big adcompared with controls. Random malformed and control fetuses means that vantage for metabonomics studies because variations in metabolites due to differwe can start to track these changes back it is a holistic approach that detects many ent diet or lifestyle factors will be cast into other biofluids,” says Gil. “Then we different types of metabolites,” explains out and will not confuse our reading of might be able to detect malformations and Gil. “We can detect sugars, organic acids, the results.” other pregnancy-related disorders by amino acids, and other types of metaboOPLS-DA of CPMG and diffusion-edsimple blood or urine screening.” lites and their derivatives in one fast, ited 1H-NMR spectra uncovered signifi—Laura Cassiday 15-20-minute experiment.”
10.1021/pr9005124
© 2009 American Chemical Society
Journal of Proteome Research • Vol. 8, No. 8, 2009 3787
