The perinatal transition of the circulating metabolome in a nonhuman primate

Beckstrom, Andrew C.; Tanya, Pattaraporn; Humston, Elizabeth M.; Snyder, L.R.; Synovec, Robert E.; Juul, Sandra E.

doi:10.1038/pr.2011.74

Cited by 21 publications

(25 citation statements)

References 35 publications

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“…Cross-sectional approaches in non-human primates have been completed to identify metabolites correlated with age (Muehlenbein et al 2003; Kuehnel et al 2012). However, longitudinal studies of metabolites in primates have been confined to earlier developmental stages (Higley et al 1992; Beckstrom et al 2012). Research in model organisms show that the analysis of metabolites has the potential to identify metabolic pathways that might be implicated in aging (Fuchs et al 2010; Houtkooper et al 2011; Hoffman et al 2014).…”

Section: Introductionmentioning

confidence: 99%

A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus

Hoffman

Tran

Wachtman

et al. 2016

Experimental Gerontology

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Primates tend to be long-lived for their size with humans being the longest lived of all primates. There are compelling reasons to understand the underlying age-related processes that shape human lifespan. But the very fact of our long lifespan that makes it so compelling, also makes it especially difficult to study. Thus, in studies of aging, researchers have turned to non-human primate models, including chimpanzees, baboons, and rhesus macaques. More recently, the common marmoset, Callithrix jacchus, has been recognized as a particularly valuable model in studies of aging, given its small size, ease of housing in captivity, and relatively short lifespan. However, little is known about the physiological changes that occur as marmosets age. To begin to fill in this gap, we utilized high sensitivity metabolomics to define the longitudinal biochemical changes associated with age in the common marmoset. We measured 2104 metabolites from blood plasma at three separate time points over a 17-month period, and we completed both a cross-sectional and longitudinal analysis of the metabolome. We discovered hundreds of metabolites associated with age and body weight in both male and female animals. Our longitudinal analysis identified age-associated metabolic pathways that were not found in our cross-sectional analysis. Pathways enriched for age-associated metabolites included tryptophan, nucleotide, and xenobiotic metabolism, suggesting these biochemical pathways might play an important role in the basic mechanisms of aging in primates. Moreover, we found that many metabolic pathways associated with age were sex specific. Our work illustrates the power of longitudinal approaches, even in a short time frame, to discover novel biochemical changes that occur with age.

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Section: Introductionmentioning

confidence: 99%

A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus

Hoffman

Tran

Wachtman

et al. 2016

Experimental Gerontology

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“…We previously examined changes in plasma metabolite concentrations in nonhuman primates associated with normal birth compared to animals exposed to perinatal asphyxia [9,10]. Several of the metabolites detected in this previous analysis were also identified in the current report, including myo -inositol and glutamate, and also arachidonic, fumaric, succinic, propanoic and erythropentonic acid.…”

Section: Discussionmentioning

confidence: 54%

“…The primate UCO model of HIE was developed to provide translational information about the metabolic, neurologic, and behavioral consequences of birth asphyxia [7,8,10]. Consistent with those reports, UCO produced moderate-to-severe HIE manifested by abnormal physical findings and blood gas parameters that satisfied established entry criteria used to qualify human infants in trials studying therapeutic hypothermia [5,6].…”

Section: Discussionmentioning

confidence: 96%

“…Plasma metabolites were extracted, derivatized and detected using 2D gas chromatography coupled with time-of-flight mass spectrometry (GC × GC–TOFMS), as previously described [10]. Metabolites were identified using Chroma time of flight (TOF) software (LECO Corp., St. Joseph, MI) and analyzed with a parallel factor analysis (PARAFAC) algorithm to determine the m/z peak signal intensity normalized to total ion current.…”

Section: Methods and Animalsmentioning

confidence: 99%

“…The UCO model has enabled us to associate HIE with poor developmental outcomes [7], directly test the effects of combined neurotherapeutic treatments on developmental brain injury [8], and to characterize the circulating metabolome to identify potential biomarkers of HIE [9,10]. In an effort to produce a MRI-detectable structural brain injury pattern consistent with patterns seen in human neonates we further modified our model.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates

McAdams¹,

McPherson²,

Kapur³

et al. 2017

Dev Neurosci

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Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O₂ 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated ultrastructural white matter abnormalities, characterized by perinuclear vacuolation and axonal dilation, in 3 of 4 animals. Immunolabeling of Nogo-A, a negative regulator of neuronal growth, was not increased in the injured brains compared to 2 control animals. Using GC × GC-TOFMS, we identified metabolites previously recognized as potential biomarkers of perinatal asphyxia. The basal ganglia-thalamus-brain stem injury produced by UCO is consistent with the deep nuclear/brainstem injury pattern seen in human neonates after severe, abrupt hypoxic-ischemic insults. The UCO model permits timely detection of biomarkers associated with specific patterns of neonatal brain injury, and it may ultimately be useful for validating therapeutic strategies to treat neonatal HIE.

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Neurodevelopment and Metabolism in the Maternal-Placental-Fetal Unit

Parenti,

Schmidt,

Tancredi

et al. 2024

JAMA Netw Open

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ImportanceDisturbances in maternal, placental, and fetal metabolism are associated with developmental outcomes. Associations of maternal, placental, and fetal metabolism with subsequent neurodevelopmental outcomes in the child are understudied.ObjectiveTo investigate the metabolic associations within the maternal-placental-fetal unit and subsequent neurodevelopmental outcomes in younger siblings of children with autism spectrum disorder (ASD).Design, Setting, and ParticipantsThis cohort study was conducted within a subset of the Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) cohort. MARBLES is a prospective birth cohort of younger siblings of children with ASD assessed for neurodevelopmental outcomes at approximately age 36 months. Participants in MARBLES were recruited through the UC Davis MIND Institute. This subset of the MARBLES cohort included younger siblings born between 2009 and 2015. Maternal third trimester serum, placental tissue, and umbilical cord serum samples were collected from participants. Only pregnancies with at least 2 of these sample types were included in this analysis. Data analysis was conducted from March 1, 2023, to March 15, 2024.ExposuresQuantitative metabolomics analysis was conducted on maternal third trimester serum, as well as placental tissue and umbilical cord serum collected at delivery.Main Outcomes and MeasuresUsing the Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning, outcomes were classified as ASD, other nontypical development (non-TD), and typical development (TD).ResultsThis analysis included 100 maternal serum samples, 141 placental samples, and 124 umbilical cord serum samples from 152 pregnancies (median [IQR] maternal age, 34.6 [30.8-38.3] years; median [IQR] gestational age, 39.0 [38.6-39.7] weeks; 87 [57.2%] male infants). There was no evidence that the maternal third trimester serum metabolome was significantly associated with the other metabolomes. The placental and cord serum metabolomes were highly correlated (first latent variate pair: R2 = 0.75; P &lt; .001) and the variate scores for each tissue were significantly associated with reduced risk of non-TD (placenta: relative risk [RR], 0.13; 95% CI, 0.02-0.71; cord: RR, 0.13; 95% CI, 0.03-0.70) but not ASD (placenta: RR, 1.09; 95% CI, 0.42-2.81; cord: RR, 0.63; 95% CI, 0.23-1.73) compared with the TD reference group.Conclusions and RelevanceIn this cohort study of children with high familial risk of ASD, placental and cord serum metabolism at delivery were highly correlated. Furthermore, placental and cord serum metabolic profiles were associated with risk of non-TD.

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The perinatal transition of the circulating metabolome in a nonhuman primate

Cited by 21 publications

References 35 publications

A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus

A longitudinal analysis of the effects of age on the blood plasma metabolome in the common marmoset, Callithrix jacchus

Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates

Neurodevelopment and Metabolism in the Maternal-Placental-Fetal Unit

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