Metabolome-wide association study of phenylalanine in plasma of common marmosets

Abstract

Little systematic knowledge exists concerning the impacts of cumulative lifelong exposure, termed the exposome, on requirements for nutrients. Phenylalanine (Phe) is an essential dietary amino acid with an aromatic ring structure similar to endogenous metabolites, dietary compounds and environmental agents. Excess plasma Phe in genetic disease or nutritional deficiency of Phe has adverse health consequences. In principle, structurally similar chemicals interfering with Phe utilization could alter Phe requirement at an individual level. As a strategy to identify components of the exposome that could interfere with Phe utilization, we tested for metabolites correlating with Phe concentration in plasma of a non-human primate species, common marmosets (Callithrix jacchus). The results of tests for more than 5000 chemical features detected by high-resolution metabolomics showed 17 positive correlations with Phe metabolites and other amino acids. Positive and negative correlations were also observed for 33 other chemicals, which included matches to endogenous metabolites and dietary, microbial and environmental chemicals in database searches. Chemical similarity analysis showed many of the matches had high structural similarity to Phe. Together, the results show that chemicals in marmoset plasma could impact Phe utilization. Such chemicals could contribute to early lifecycle developmental disorders when neurological development is vulnerable to Phe levels.

High-resolution metabolomics of occupational exposure to trichloroethylene

“…In this study, we used a metabolome-wide association study (MWAS) 30 , 36 , 37 to identify dose-dependent metabolic changes in TCE-exposed workers and unexposed controls, using a well-characterized, worker population 17 , 19 . Direct TCE and endogenous metabolites were characterized, and pathway analysis was used to identify biological response to TCE exposure.…”

High-Resolution Metabolomics Assessment of Military Personnel

“…A limitation is that these analyses do not provide absolute chemical identity for most of the ions detected. Confirmation of chemical identities with tandem mass spectral (MS/MS) analysis and co-elution with authentic standards has been performed for several hundred chemicals in other studies using these methods (7–12,14,16,45, 51)) and provide confidence that the conclusions reached are valid, even though many individual ion matches are incorrect.…”

Putrescine as indicator of manganese neurotoxicity: Dose-response study in human SH-SY5Y cells

“…Electrospray ionization was used in the positive ion mode on the Q-Exactive HF mass spectrometer operating with resolution set to 120,000 and scan range set to 85–1275 m/z (mass to charge) (Liu et al, 2016; Soltow et al, 2013). Ultra-high resolution mass spectrometry operating at 60,000 and 120,000 resolution have previously been shown to provide effective quantification of metabolites in biologic extracts (Accardi et al, 2016; Go et al, 2015b, 2015c, 2015d; Johnson et al, 2008). A 2% formic acid/acetonitrile gradient was used as described (Liu et al, 2016).…”

“…However, these do not yet have sufficient theoretical or experimental development for application to nutritional assessment. For instance, high-resolution metabolomics (HRM) (Walker et al, 2016) supports both targeted analysis of nutrients (Accardi et al, 2016) and also targeted metabolome-wide association study (MWAS) to discover metabolites and metabolic pathways that vary in association with an essential nutrient (Go et al, 2015d). In principle, this 3-step approach [ 1) experimental variation in a nutrient, 2) targeted analysis of a metabolite expected to change and 3) MWAS of the targeted metabolite] provides a way to map out diverse metabolic networks associated with variation in specific nutrients.…”