Dataset Information

Multiomic Profiling of Iron Deficient Infant Monkeys Reveals Alterations in Neurologically Important Biochemicals in Serum and CSF Prior to the Onset of Anemia

ABSTRACT: Background: The effects of iron deficiency anemia (IDA) during infancy extend beyond the hematologic compartment and include short- and long-term adverse effects on many tissues including the brain. However, biomarkers of iron-dependent brain health are lacking in humans. Prior analyses in rhesus infants indicated abnormal serum and cerebral spinal fluid (CSF) multiomic profiles both prior to and during IDA, characterized by alterations suggestive of hepatic and brain metabolic dysfunction, and impaired energy metabolism. Objective: To determine whether serum and CSF biomarkers of iron deficiency (ID)-induced metabolic dysfunction are concordant in the pre/early anemic stage of ID in a nonhuman primate model of infantile IDA. Methods: Paired serum and CSF specimens were collected from iron-sufficient (IS; n = 12) and ID (n = 7) rhesus infants at 4-months (preanemic period) and 6-months (anemic period) of age. Hematological, metabolomic, and proteomic profiles were generated via HPLC/MS at both timepoints to discover serum biomarkers of ID-induced brain metabolic dysfunction. Results: We identified and quantified 227 metabolites and 205 proteins in serum. Abnormalities indicating altered liver function, lipid dysregulation, and increased acute phase proteins were present in ID. In CSF, we measured 210 metabolites and 1,560 proteins with ID infants displaying metabolomic and proteomic changes indicating disrupted synaptogenesis. Concurrent systemic and CSF proteomic and metabolomic changes were present in the preanemic and anemic periods. Conclusions: Multiomic serum and CSF profiling uncovered pathways disrupted by ID in both the preanemic and anemic stages of infantile IDA, including evidence for liver metabolic dysfunction and acute phase responses. Parallel changes observed in serum and CSF potentially provide measurable serum biomarkers that reflect at-risk brain processes early during ID.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Macaca Mulatta (rhesus Macaque)

TISSUE(S): Cerebrospinal Fluid, Blood Serum

DISEASE(S): Iron Deficiency Anemia

SUBMITTER: Brian Sandri

LAB HEAD: Raghavendra Rao

PROVIDER: PXD028275 | Pride | 2022-03-18

REPOSITORIES: Pride

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	Mudpit_raghurao_sand0449_20191220_17561_TMT1__raghurao_sand0449_20191220_17561_TMT_01.mzid.gz	Mzid
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	Mudpit_raghurao_sand0449_20191228_17563_TMT3__raghurao_sand0449_20191228_17563_TMT3_01.mzid.gz	Mzid

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Multiomic profiling of iron-deficient infant monkeys reveals alterations in neurologically important biochemicals in serum and cerebrospinal fluid before the onset of anemia.

Sandri Brian J BJ Kim Jonathan J Lubach Gabriele R GR Lock Eric F EF Guerrero Candace C Higgins LeeAnn L Markowski Todd W TW Kling Pamela J PJ Georgieff Michael K MK Coe Christopher L CL Rao Raghavendra B RB

American journal of physiology. Regulatory, integrative and comparative physiology 20220310 6

The effects of iron deficiency (ID) during infancy extend beyond the hematologic compartment and include short- and long-term adverse effects on many tissues including the brain. However, sensitive biomarkers of iron-dependent brain health are lacking in humans. To determine whether serum and cerebrospinal fluid (CSF) biomarkers of ID-induced metabolic dysfunction are concordant in the pre/early anemic stage of ID before anemia in a nonhuman primate model of infantile iron deficiency anemia (IDA ...[more]

PMID: 35271351

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Project description:Background: Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown. Objective: We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Methods: Fischer344/Jcl male rats aged 21–39 days were fed low-iron diets (0.35 mg/kg iron; ID group) or standard AIN-93 G diets (3.5 mg/kg iron; control group). The locomotor activity of male offspring was evaluated by the open field and elevated plus maze tests at ages 8 and 12 weeks. Monoamine concentrations in the PFC, NAcc, caudate-putamen, ventral midbrain, dorsal midbrain, and pons were analyzed. Comprehensive gene expression analysis was performed in the PFC and NAcc at age 13 weeks. Finally, we investigated synaptic density in the PFC and NAcc by synaptophysin immunostaining. Results: Behavioral tests revealed significant interactions between age and iron consumption for the total distance traveled and the distance traveled in the peripheral area (p < 0.05), indicating that ID during the juvenile period affected hyperactivity and that this persisted to adulthood. At age 13 weeks, the ID group had increased levels of both dopamine and the metabolites of dopamine and serotonin in the NAcc. Comprehensive gene expression analysis and immunostaining showed decreased Reelin gene expression (adjusted p < 0.01) and significantly increased spine density in the NAcc in the ID group compared with the control group (p < 0.01). Conclusions: ID during the postweaning juvenile period led to long-term hyperactivity, monoamine disturbance in the brain, and downregulation of Reelin expression in the NAcc despite complete iron repletion. Epigenetic modification of Reelin genes may be involved in synaptic plasticity in the NAcc.