Prepubertal exposure to high dose of cadmium induces hypothalamic injury through transcriptome profiling alteration and neuronal degeneration in female rats

• Published in: Chemico-biological interactions Vol. 337; p. 109379
• Main Authors: Saedi, Saman, Jafarzadeh Shirazi, Mohammad Reza, Niazi, Ali, Tahmasebi, Ahmad, Ebrahimie, Esmaeil
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2021
• Subjects: Animals; Arcuate Nucleus of Hypothalamus - drug effects; Arcuate Nucleus of Hypothalamus - metabolism; Arcuate Nucleus of Hypothalamus - pathology; Blood Glucose - analysis; Cadmium; Cadmium Chloride - toxicity; Down-Regulation - drug effects; Female; Gene Ontology; Gene Regulatory Networks - drug effects; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Hypothalamus - pathology; Immune System - drug effects; Immune System - metabolism; Neurological disorders; Neuropeptides - genetics; Neuropeptides - metabolism; Prepubertal female rat; Prolactin - blood; Rats; Rats, Sprague-Dawley; RNA-Seq; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome - drug effects; Transcriptome profiling; Up-Regulation - drug effects; Cadmium; Prepubertal female rat; Hypothalamus; Transcriptome profiling; RNA-Seq; Neurological disorders
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2021.109379

Cadmium (Cd) is a toxic metal, which seems to be crucial during the prepubertal period. Cd can destroy the structural integrity of the blood-brain barrier (BBB) and enters into the brain. Although the brain is susceptible to neurotoxicity induced by Cd, the effects of Cd on the brain, particularly hypothalamic transcriptome, are still relatively poorly understood. Therefore, we investigated the molecular effects of Cd exposure on the hypothalamus by profiling the transcriptomic response of the hypothalamus to high dose of Cd (25 mg/kg bw/day cadmium chloride (CdCl2)) during the prepubertal period in Sprague-Dawley female rats. After sequencing and annotation, differential expression analysis revealed 1656 genes that were differentially expressed that 108 of them were classified into 37 transcription factor (TF) families. According to gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, these differentially expressed genes (DEGs) were involved in different biological processes and neurological disorders including Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), prolactin signaling pathway, PI3K/Akt signaling, and dopaminergic synapse. Five transcripts were selected for further analyses with Real-time quantitative PCR (RT-qPCR). The RT-qPCR results were mostly consistent with those from the high throughput RNA sequencing (RNA-seq). Cresyl violet staining clearly showed an increased neuronal degeneration in the dorsomedial hypothalamus (DMH) and arcuate (Arc) nuclei of the CdCl2 group. Overall, this study demonstrates that prepubertal exposure to high doses of Cd induces hypothalamic injury through transcriptome profiling alteration in female rats, which reveals the new mechanisms of pathogenesis of Cd in the hypothalamus. •Prepubertal exposure to Cd altered expression of 1656 hypothalamic genes.•Cd altered genes expression involved in neurological disorders including AD, HD, and PD.•Cd induced upregulation of Esr1 in the hypothalamus while decreased E2 hormone.•Cd exposure induced neuronal degeneration in the hypothalamus of female rats.•Dopaminergic synapse, PI3K/Akt, and prolactin signaling pathways are enriched with altered genes.