Nonhuman primate breath volatile organic compounds associate with developmental programming and cardio-metabolic status

Abstract

Rodent and nonhuman primate studies indicate that developmental programming by reduced perinatal nutrition negatively impacts life course cardio-metabolic health. We have developed a baboon model in which we feed control mothers (CON) ad libitum while nutrient restricted mothers are fed 70% of ad libitum global feed in pregnancy and lactation. Offspring of nutrient restricted mothers are intrauterine growth restricted (IUGR) at term. By 3.5 years IUGR baboons showed signs of insulin resistance, indicating a pre-diabetic phenotype, in contrast to healthy CON offspring. We hypothesized that a novel breath analysis approach would provide markers of the altered cardio-metabolic state in a non-invasive manner. Here we assess whether exhaled breath volatile organic compounds (VOCs) collected from this unique cohort of juvenile baboons with documented cardio-metabolic dysfunction resulting from in utero programming can be detected from their breath signatures. Breath was collected from male and female CON and IUGR baboons at 4.8 ± 0.2 years (human equivalent ∼13 years). Breath VOCs were quantified using a two-dimensional gas chromatography mass spectrometer. Two-way ANOVA, on 76 biologically relevant VOCs identified 27 VOCs (p < 0.05) with altered abundances between groups (sex, birthweight, and sex x birthweight). The 27 VOCs included 2-pentanone, 2-octanone, 2,2,7,7-tetramethyloctane and 3-methyl-1-heptene, which have not previously been associated with cardio-metabolic disease. Unsupervised principal component analysis of these VOCs could discriminate the four clusters defining males, females, CON and IUGR. This study, which is the first to assess quantifiable breath signatures associated with cardio-metabolic programing for any model of IUGR, demonstrates the translational value of this unique model to identify metabolites of programmed cardio-metabolic dysfunction in breath signatures. Future studies are required to validate the translatability of these findings to humans.

Sex-dependent vulnerability of fetal nonhuman primate cardiac mitochondria to moderate maternal nutrient reduction

“…We have developed a well-established nonhuman IUGR primate model to evaluate the effects of moderate maternal nutrient reduction (MNR) in which baboon mothers were fed 70% of the global diet eaten by controls fed ad libitum during pregnancy and lactation (10)(11)(12)(13)(14)(15). At birth, MNR offspring were IUGR weighing ~89% of control offspring (16).…”

Breath biomarkers of insulin resistance in pre-diabetic Hispanic adolescents with obesity

“…By implementing a machine learning model to assess the normalized data, a predictive model based on the selected features could be built to inform diagnostic potential of exhaled breath signatures. Our previous studies in nonhuman primates identified exhaled breath signatures in animals with IR 19 . The adoption of the HOMA-IR categories was based on a population-based study reported from the adult Mexican Americans population 21 , as no clear definition exist for the Hispanic adolescents with IR.…”

“…Although the other six breath metabolites did not reach significance between the groups individually (Supplementary Figure S5), their contribution to the breath-IR model is evident when assessing the diagnostic capability of the model (Figure 5) to identify individuals with IR. A combined signature of breath metabolites is clearly more informative than using a single metabolite which may be indicative of some normal variability in metabolites within and between individuals 15,19,42 .…”

“…Following the development of IR, a volatile organic compound (VOC) breath signature was identified that discriminated between NHPs with IR compared to controls. It is suggested the altered breath signature arose from an altered cardiometabolic state potentially due to increased ROS production, beta-oxidation, inflammation, and lipid peroxidation 19 . Based on these findings, we hypothesized that metabolic markers contained in exhaled breath could be a potential diagnostic resource for defining metabolic status in humans and furthermore could be used to diagnose IR in pre-diabetic adolescents.…”

Metabolic Reprogramming: Short-term Western Diet Exposure Induces Sustained Changes in Plasma Metabolites

“…Non-human primate (NHP) models, such as baboons, have been used extensively to study cardiometabolic disorders in response to Western and other diets [14][15][16][17]. These studies benefit from the similarity in metabolism and nutritional needs of these animals compared to humans, and a controlled environment in which diets of defined composition can be fed without having to account for variable prior exposures of animals.…”