Cadmium accumulation and metallothionein expression in brain of mice at different stages of development

doi:10.1016/0378-4274(95)03444-7

Toxicology Letters

Volume 84, Issue 3, March 1996, Pages 127-133

https://doi.org/10.1016/0378-4274(95)03444-7 Get rights and content

Abstract

Cadmium accumulation and metallothionein (MT) expression were studied in brains of adult mice as well as at different stages of development. MT expression was also studied in the eye of adult mice as well as at different stages of development. Using northern blot analysis with total RNA, MT mRNAs were not detected in day 16 through day 18 embryos or in postnatal animals up to day 14. Detectable expression of MT-I, -II, and -III mRNAs was obtained in brains of 30- and 60-day-old mice. The expression of MT-III mRNA appeared to be much stronger in adults (12 weeks old or more) than in 30- and 60-day-old animals. In contrast, there was similar expression of MT-I and -II in 30- and 60-day-old mice. Cd distribution to brain was found to decrease with age; the brains of 7-day-old mice contained about 4-times more Cd than that of adult mice. Thus, an inverse correlation was observed between MT expression and Cd accumulation in brain.

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2021, Science of the Total Environment
Citation Excerpt :
The Cd can penetrate into the brains of newborn animals, which decrease with age. This is perhaps due to increase in expression of MT's and development of the blood brain barrier (Choudhuri et al., 1996). MTs are actually responsible for detainment of cadmium in the tissues and for the prolonged biological half-life of Cd in the body.
Metallothioneins (MTs) are small metalloproteins that contain cysteine residues and provide excellent feasibility for binding metals. They have low molecular mass and are known to carry out a plethora of functions including metal homeostasis, scavenging free radicals, and shield against heavy metals. The expression levels of these peptides among invertebrates and aquatic vertebrates have compelled researchers all over the world to study MTs as a promising solution for resolving heavy metal contamination. The role of MTs in cadmium disposition, poisoning, toxicity, carcinogenesis, and its biokinetics have been exhaustively studied, along with the various analytical methods used to characterize these peptides. Although, classically, various natural biological processes are being carried out by these metal-binding proteins, they are now being exploited as bio-environmental markers for predicting heavy metal contamination based on their levels of expression. This review focuses on MTs by elaborating on its structural and chemical characterization, a comprehensive overview of the notable techniques being utilized for quantification and purification of such peptides and its applications in various fields.
Prepubertal exposure to high dose of cadmium induces hypothalamic injury through transcriptome profiling alteration and neuronal degeneration in female rats
2021, Chemico-Biological Interactions
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.
Association between prenatal cadmium exposure and cognitive development of offspring: A systematic review
2019, Environmental Pollution
Citation Excerpt :
Studies have indicated that Cd may be associated with adverse effects in brain development. Two studies (Choudhuri et al., 1996; Wong et al., 1980) also reported that the accumulation of Cd in newborn mice or rats was significantly higher than it in adult animals. In an epidemiological study, a higher concentration of hair Cd in children was reported to be associated with neurobehavioral impairments (Marlowe et al., 1983) and learning difficulties and/or dyslexia (Capel et al., 1981; Pihl and Parkes, 1977).
Due to the lack of substantial and reliable evidence on the relationship between prenatal cadmium (Cd) exposure and cognitive development of offspring, we conducted the present systematic review. Leading electronic databases—including Pubmed, Embase, Web of Science, the Cochrane Library, PsycINFO, PsycARTICLES, and the Psychology and Behavioral Sciences Collection—were searched on February 14, 2019. There was no date, study design or language limit imposed in our search. All of the included studies satisfied our predetermined study population (pregnant mothers and their offspring), exposure (prenatal Cd exposure), and outcome measurements (adverse effects on cognitive development). The quality assessment for the included studies was conducted with the Newcastle-Ottawa Scale (NOS). Nine prospective cohort studies met the inclusion criteria, and six of them were assessed to be of high quality based on the NOS (NOS score ≥ 7). The prenatal Cd exposure was tested in maternal blood samples (4/9), umbilical cord blood samples (4/9), or maternal urinary samples (3/9). Among the nine studies included, six reported at least one inverse association between prenatal Cd exposure and the cognitive development of offspring, mainly in terms of language development (4/8), performance ability development (3/5), and general cognitive development (3/8). Furthermore, among six studies with high methodological quality (NOS score ≥ 7), prenatal Cd exposure was reported to be associated with language development in three studies (3/5), performance ability development in three studies (3/4), and general cognitive development in three studies (3/5). This systematic review provides convincing evidence that prenatal exposure to Cd is inversely associated with neurodevelopment of offspring. Larger prospective studies using standardized criteria and assessments of cognitive development are needed to confirm the dose-response effect and gender difference of prenatal Cd exposure on cognitive development of offspring.
Hormonal changes and folliculogenesis in female offspring of rats exposed to cadmium during gestation and lactation
2018, Environmental Pollution
It has been suggested that the toxic effects of cadmium (Cd) may disrupt ovarian and uterine functions in adults. However, Cd exposure during gestation and lactation and its effects on the reproductive development in female offspring is still not clear, and the mechanisms underlying exposure toxicology remain mostly unexplored. To investigate how Cd exposure of female rats (F0) during gestation and lactation affects the reproductive development of their female offspring, we studied the steroidogenesis, folliculogenesis, puberty onset, and litter size of the first (F1) and second (F2) filial generations following F0 female rats which had been exposed to CdCl₂. The mechanisms related to the early onset of puberty induced by such exposure in female offspring were explored. Maternal exposure to Cd dramatically increased the biosynthesis of steroid hormones in F1 female offspring by the activation of cAMP/PKA pathway and up-regulated expression of steroidogenesis related proteins such as StAR, CYP11A1, 3β-HSD and CYP19A1. The high levels of steroid hormones contributed to an early puberty onset, promoted the differentiation and maturation of follicles, and led to the proliferation of endometrium that resulted in a uterus weight gain. The increased number of antral follicles eventually caused a big litter size. Despite of being free from additional Cd exposure, the levels of CYP11A1 and CYP19A1 in the ovaries of F2 female rats were also high, which resulted in a high concentration of serum progesterone. These results suggested that hormonal changes induced by exposure to Cd in utero might have a lasting effect beyond the first generation. These findings may help to better understand the origin of female sexual dysfunction in the developmental stages in general.
The developmental neurotoxicity of cadmium
2018, Handbook of Developmental Neurotoxicology
Cadmium (Cd²⁺) is a heavy metal that occurs naturally in the earth’s crust and artificially through industrial processes. It has been widely established that Cd²⁺ adversely affects various bodily systems and organs, in particular, the kidneys; however, the harmful effects of Cd²⁺ on the developing nervous system have garnered substantial attention more recently. Numerous animal studies have demonstrated that Cd²⁺ accumulates in the developing brain, induces oxidative stress, and alters neurotransmitter and electrophysiological activity. They have also shown that Cd²⁺ impairs the activity of enzymes responsible for healthy cellular functioning in various brain regions. These neurochemical changes are often accompanied by unfavorable neurobehavioral outcomes. In recent human studies, prenatal and postnatal Cd²⁺ exposure has been found to predict poorer outcomes on measures of behavior, cognition, and development during childhood and adolescence. Overall, Cd²⁺ appears to pose a significant risk to the developing nervous system and measures should be taken to limit exposures to it, particularly early in life.
Effects of subchronic exposure to waterborne cadmium on H-P-I axis hormones and related genes in rare minnows (Gobiocypris rarus)
2017, Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
Citation Excerpt :
However, the neuro related tissues are capable to accumulate Cd as well. Specifilly, after Cd exposure, the Cd content in the brain of mosquito fish (Gambusia affinis) was increased (Ali et al., 2016), Cd accumulation in the brain was also observed in common carp (Karaytug et al., 2007) and mice (Choudhuri et al., 1996). What's more, accumulated Cd can damage the pituitary cells of the lizard (Podarcis sicula) (Ferrandino et al., 2010).
The H (hypothalamic)-P (pituitary)-I (interrenal) axis is critical in the stress response and other activities of fish. To further investigate cadmium (Cd) toxicity on the H-P-I axis and to identify its potential regulatory genes in fish, the adult female rare minnows (Gobiocypris rarus) were exposed to subchronic (5 weeks) levels of waterborne Cd in the present study. This kind of treatment caused dose-dependent decline in fish growth, with significance in the high dose group (100 μg/L). Correspondingly, low dose (5–50 μg/L) waterborne Cd disrupted the endocrine system of H-P-I axis just at the secretion level, while high dose Cd disrupted both the secretion and synthesis of cortisol and its downstream signals in rare minnows, revealed by the significantly upregulation and positive correlation of corticosteroidogenic genes including MC2R, StAR, CYP11A1, and CYP11B1 in the kidney (including the interrenal tissue) (P < 0.05), and the significant alteration of Glcci1, Hsp90AA and Hsp90AB in the hepatopancreas, gill and intestine as well (P < 0.05). The expression of Glcci1 was significantly decreased in hepatopancreas, gill and intestine of tested fish following treatment, and its positive correlation with GR (Glucocorticoid receptor) suggested its potential regulation on the cortisol and/or H-P-I axis in fish. The expression of FKBP5 in the intestine was positively and significantly correlated with that of Hsp90AA (P < 0.05), and the Hsp90AB transcript in the hepatopancreas was positively correlated with that of Hsp90AA (P < 0.05), which indicated that Hsp90AA and Hsp90AB were more likely to serve as cofactors of GR and FKBP5 in response to Cd exposure.

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^☆: Supported by NIH Grants ES-01142 and MH-38399.

¹: Present Address: Biochemical and Molecular Toxicology Group, Health and Environmental Science (HES), Dow Corning Corporation, Midland, MI 48686, USA.

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Research articleCadmium accumulation and metallothionein expression in brain of mice at different stages of development☆

Abstract

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Exp. Neurol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Life. Sci.

Toxicol. Appl. Pharmacol.

Research article
Cadmium accumulation and metallothionein expression in brain of mice at different stages of development☆