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Transcriptomic, proteomic, and metabolomic analyses identify candidate pathways linking maternal cadmium exposure to altered neurodevelopment and behavior.

ABSTRACT: Cadmium (Cd) is a ubiquitous toxic heavy metal of major public concern. Despite inefficient placental transfer, maternal Cd exposure impairs fetal growth and development. Increasing evidence from animal models and humans suggests maternal Cd exposure negatively impacts neurodevelopment; however, the underlying molecular mechanisms are unclear. To address this, we utilized multiple -omics approaches in a mouse model of maternal Cd exposure to identify pathways altered in the developing brain. Offspring maternally exposed to Cd presented with enlarged brains proportional to body weights at birth and altered behavior at adulthood. RNA-seq in newborn brains identified exposure-associated increases in Hox gene and myelin marker expression and suggested perturbed retinoic acid (RA) signaling. Proteomic analysis showed altered levels of proteins involved in cellular energy pathways, hypoxic response, and RA signaling. Consistent with transcriptomic and proteomic analyses, we identified increased levels of retinoids in maternally-exposed newborn brains. Metabolomic analyses identified metabolites with significantly altered abundance, supportive of changes to cellular energy pathways and hypoxia. Finally, maternal Cd exposure reduced mitochondrial DNA levels in newborn brains. The identification of multiple pathways perturbed in the developing brain provides a basis for future studies determining the mechanistic links between maternal Cd exposure and altered neurodevelopment and behavior.

SUBMITTER: Hudson KM

PROVIDER: S-EPMC8357970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: Identify gene expression changes in whole brains of newborn pups whose mothers were exposed to Cd during pregnancy (50ppm CdCl2) compared to unexposed controls (0ppm CdCl2). Methods: 5- to 7-week-old C57BL/6J (‘B’) and CAST/EiJ (‘C’) females (the F0 generation) were exposed through their drinking water to 0 ppm or 50 ppm Cd in the form of CdCl2 (Sigma-Aldrich, catalog number 202908) for a period of 5 weeks, then mated with a male of the opposite strain. Cd exposure continued throughout pregnancy and was discontinued at litter birth. A hybrid mating scheme (the F1 generation) was employed to enable analyses of allele-specific gene expression and DNA methylation for a separate study (Hudson & Cowley, manuscript in preparation). The genotypes of F1 mice are referred to as ‘BxC’ (B mother x C father). F1 animals were sacrificed and dissected within 24 hours of birth; sample sizes can be found in supplementary tables associated with the publication. F1 mice were dissected within 24 hours of birth. All animal work was approved by the North Carolina State University (NCSU) Institutional Animal Care and Use Committee, under protocol 16-045-B. All experiments were conducted in accordance with the Guiding Principles in the Use of Animals in Toxicology. Frozen whole brains obtained from four 0 ppm and four 50 ppm newborn female BxC pups representing four litters per exposure group were pulverized using a hammer and liquid nitrogen. 7-10 mg of tissue was then used to extract DNA and RNA simultaneously using the AllPrep DNA/RNA/miRNA kit (Qiagen, 80204). RNA was extracted using the recommended protocol for fatty tissues. RNA and DNA were quantified using a Nanodrop 2000. RNA purity and size integrity were determined at the NCSU Genomic Sciences Laboratory (GSL) using an Agilent 2100 Bioanalyzer with an RNA 6000 Nano Chip (Agilent Technologies). Results: We identified 15 significantly differentially expressed genes (DEGs) that aligned to both the B and C genomes. Conclusions: These 15 DEGs (and subsequent confirmatory qRT-PCRs on the 8 samples sequenced here plus an additional Cd dose and samples) suggest altered onset of myelination throughout the whole brain, as well as aberrant Hox gene expression due to maternal Cd exposure.

Project description:Cystinosis is a rare, devastating hereditary disease secondary to recessive CTNS gene mutations. The most commonly used diagnostic method is confirmation of an elevated leukocyte cystine level; however, this method is expensive and difficult to perform. This study aimed to identify candidate biomarkers for the diagnosis and follow-up of cystinosis based on multiomics studies. The study included three groups: newly-diagnosed cystinosis patients (patient group, n = 14); cystinosis patients under treatment (treatment group, n = 19); and healthy controls (control group, n = 30). Plasma metabolomics analysis identified 10 metabolites as candidate biomarkers that differed between the patient and control groups [L-serine, taurine, lyxose, 4-trimethylammoniobutanoic acid, orotic acid, glutathione, PE(O-18:1(9Z)/0:0), 2-hydroxyphenyl acetic acid, acetyl-N-formil-5-metoxikinuramine, 3-indoxyl sulphate]. As compared to the healthy control group, in the treatment group, hypotaurine, phosphatidylethanolamine, N-acetyl-d-mannosamine, 3-indolacetic acid, p-cresol, phenylethylamine, 5-aminovaleric acid, glycine, creatinine, and saccharic acid levels were significantly higher, and the metabolites quinic acid, capric acid, lenticin, xanthotoxin, glucose-6-phosphate, taurine, uric acid, glyceric acid, alpha-D-glucosamine phosphate, and serine levels were significantly lower. Urinary metabolomic analysis clearly differentiated the patient group from the control group by means of higher allo-inositol, talose, glucose, 2-hydroxybutiric acid, cystine, pyruvic acid, valine, and phenylalanine levels, and lower metabolite (N-acetyl-L-glutamic acid, 3-aminopropionitrile, ribitol, hydroquinone, glucuronic acid, 3-phosphoglycerate, xanthine, creatinine, and 5-aminovaleric acid) levels in the patient group. Urine metabolites were also found to be significantly different in the treatment group than in the control group. Thus, this study identified candidate biomarkers that could be used for the diagnosis and follow-up of cystinosis.

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Transcriptomic, proteomic, and metabolomic analyses identify candidate pathways linking maternal cadmium exposure to altered neurodevelopment and behavior.

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