Low-dose Cd Research Articles

A single-cell transcriptomic landscape of cadmium-hindered brain development in mice

The effects of neurotoxicant cadmium (Cd) exposure on brain development have not been well elucidated. To investigate this, we have herein subjected pregnant mice to low-dose Cd throughout gestation. Using single-cell RNA sequencing (scRNA-seq), we explored the cellular responses in the embryonic brain to Cd exposure, and identified 18 distinct cell subpopulations that exhibited varied responses to Cd. Typically, Cd exposure impeded the development and maturation of cells in the brain, especially progenitor cells such as neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). It also caused significant cell subpopulation shifts in almost all the types of cells in the brain. Additionally, Cd exposure reduced the dendritic sophistication of cortical neurons in the offspring. Importantly, these changes led to aberrant Ca2+ activity in the cortex and neural behavior changes in mature offspring. These data contribute to our understanding of the effects and mechanisms of Cd exposure on brain development and highlight the importance of controlling environmental neurotoxicant exposure at the population level.

Cadmium promoted LPS-induced inflammation through TLR4/IκBα/NFκ-B signaling by increasing ROS-mediated incomplete autophagy

Cadmium (Cd) exposure is considered as non-infectious stressor to human and animal health. Recent studies suggest that the immunotoxicity of low dose Cd is not directly apparent, but disrupts the immune responses when infected with some bacteria or virus. But how Cd alters the adaptive immunity organ and cells remains unclear. In this study, we applied lipopolysaccharide (LPS, infectious stressor) to induced inflammation in spleen tissues and T cells, and investigated the effects after Cd exposure and the underlying mechanism. Cd exposure promoted LPS-induced the expressions of the inflammatory factors, induced abnormal initiation of autophagy, but blocked autophagic flux. The effects Cd exposure under LPS activation were reversed by the autophagy promoter Rapamycin. Under LPS activation conditions, Cd also induced oxidative stress by increasing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and reducing total antioxidant capacity (T-AOC) activity. The increased superoxide dismutase (SOD) activity after Cd exposure might be a negative feedback or passive adaptive regulation of oxidative stress. Cd-increased autophagic flux inhibition and TNF-α expression were reversed by ROS scavenger α-tocopherol (TCP). Furthermore, under LPS activation condition, Cd promoted activation of toll-like receptor 4 (TLR4)/IκBα/NFκ-B signaling pathway and increased TLR4 protein stability, which were abolished by the pretreatment of Rapamycin. The present study confirmed that, by increasing ROS-mediated inhibiting autophagic degradation of TLR4, Cd promoted LPS-induced inflammation in spleen T cells. This study identified the mechanism of autophagy in Cd-aggravated immunotoxicity under infectious stress, which could arouse public attention to synergistic toxicity of Cd and bacterial or virus infection.

EIF4A3 modulated circ_000999 promotes epithelial-mesenchymal transition in cadmium-induced malignant transformation through the miR-205-5p/ZEB1 axis

Cadmium (Cd) is an accumulative toxic metal which poses a serious threat to human health, even in trace amounts. One of the most important steps in the pathophysiology of lung cancer (LC) is the epithelial-mesenchymal transition (EMT). In this investigation, a cell malignant transformation model was established by exposing human bronchial epithelial cells (16HBE) to a low dose of Cd for 30 weeks, after which a highly expressed circular RNA (circ_000999) was identified. Cd-induced EMT was clearly observed in rat lungs and 16HBE cells, which was further enhanced following circ_000999-overexpression. Furthermore, upregulated EIF4A3 interacted with the parental gene AGTPBP1 to promote high expression of circ_000999. Subsequent experiments confirmed that circ_000999 could regulate the EMT process by competitively binding miR-205-5p and inhibiting its activity, consequently upregulating expression of zinc finger E-box binding protein 1 (ZEB1). Importantly, the circ_000999 expression level in LC tissues was significantly increased, exhibiting a strong correlation with EMT indicators. Overall, these findings provide a new objective and research direction for reversing lung EMT and subsequent treatment and prevention of LC.

Nanoplastics increase algal absorption and toxicity of Cd through alterations in cell wall structure and composition

Nanoplastics (NPs) may act as carriers of heavy metals and cause complex toxicity to aquatic organisms, while the exact role of NPs in the joint toxicity remains unclear. Here, we investigated the joint toxicity of polystyrene NPs (PS-NPs) and Cd to freshwater algae (Chlorella vulgaris). It was found that PS-NPs (1 mg L−1) could hardly enter algal cells and slightly inhibit algal growth (p < 0.01). The effect of PS-NPs as carriers on the joint toxicity of PS-NPs and heavy metals could be neglected because of the limited adsorption of Cd by PS-NPs, while the PS-NPs altered the cell wall structure and composition, which resulted in the increased algal absorption and toxicity of Cd. Compared to the low dose Cd (0.4 mg L−1) treatment alone, the extracellular and intracellular Cd contents in the cotreatment were significantly increased by 27.3 % and 18.0 %, respectively, due to the increased contents of cell wall polysaccharides (pectin and hemicellulose in particular) by the PS-NPs. Furthermore, after the high dose Cd (2 mg L−1) exposure, the inhibited polysaccharide biosynthesis and the loosen cell wall structure weakened the tolerance of cell wall to abiotic stress, facilitating the entry of PS-NPs into the algal cells and inducing the higher toxicity. These results elucidate the mechanism by which NPs enhance heavy metal toxicity to algae, providing a novel insight into environmental risks of NPs.

The effect of zinc application on growth and alleviating shoot concentration of cadmium in durum wheat plant growth under conditions of salt and cadmium stress

A study was conducted in a greenhouse to investigate the effect of the combination of cadmium (Cd) and salinity (NaCl) stress in zinc (Zn) deficiency on growth, Cd accumulation in durum wheat (Triticum turgidum L. durum, cv. Balcali-2000), and micro (Zn, Fe, Cu, Mn) minerals differing in salt tolerance. The negative effects of Cd and NaCl stress on plant growth and Cd accumulation detected to alleviate Cd uptake on wheat growth increasing zinc application. The results revealed that Cd, NaCl and their combined stresses reduced shoots dry matter and Cd concentration in shoots increased compared to control pots. In increasing Cd and NaCl treatments, increasing Zn application significantly decreased the Cd concentration in shoot. In particularly, the decrease in Cd concentration was more noticeable with the improvement of Zn nutrition of plants at low doses of NaCl and Cd. The effect of increasing zinc treatments on reducing Cd accumulation decreased to slightly at high doses of Cd and NaCl. According to the results it can be suggested that Zn application to soils with low Cd content and medium salinity can be reduce Cd uptake by durum wheat.

Heavy Metals in Poultry Chicken and Human Health Threat: A Mini Review

It has been shown that the most hazardous heavy metals that are constantly emitted into the environment are arsenic (As), lead (Pb), cadmium (Cd), and mercury (Hg). These metals can be found in both naturally occurring and artificially produced fertilizers, industrial processes, and waste disposal. Due to ongoing exposure to heavy metals, bioaccumulation of As, Pb, Cd, and Hg takes place in a variety of organs in chickens, primarily the kidneys, liver, reproductive organs, and lungs. Chemical, biological, or physical risks can be connected to animal feed. Poultry feed contamination can come from negligent or intentional handling, storage, and transportation practices. Because of the increased concentration of these heavy metals in these tissues—primarily the brain, liver, kidneys, and reproductive organs—chronic exposure to low doses of As, Pb, Cd, and Hg can alter the microscopic structure of these tissues. This puts human health at risk when consuming chicken or poultry. Risks to food safety should be carefully considered in order to reduce unfavorable side effects in both people and animals. Governments should therefore implement stringent measures to prevent any harmful contamination that could endanger public health. This review presents a discussion of bioaccumulation of As, Cd, Pb, and Hg in poultry with the associated problem of consumption of poultry and human health.

The damage caused by Cd toxicity to photosynthesis, cellular ultrastructure, antioxidant metabolism, and gene expression in young cacao plants are mitigated by high Mn doses in soil.

Manganese (Mn) is one of the essential mineral micronutrients most demanded by cacao. Cadmium (Cd) is highly toxic to plants and other living beings. There are indications that Mn can interact with Cd and mitigate its toxicity. The objective of this study was to evaluate the action of Mn on the toxic effect of Cd in young plants of the CCN 51 cacao genotype, subjected to different doses of Mn, Cd, and Mn+Cd in soil, through physiological, biochemical, molecular, and micromorphological and ultrastructural changes. High soil Mn doses favored the maintenance and performance of adequate photosynthetic processes in cacao. However, high doses of Cd and Mn+Cd in soil promoted damage to photosynthesis, alterations in oxidative metabolism, and the uptake, transport, and accumulation of Cd in roots and leaves. In addition, high Cd concentrations in roots and leaf tissues caused irreversible damage to the cell ultrastructure, compromising cell function and leading to programmed cell death. However, there was a mitigation of Cd toxicity when cacao was grown in soils with low Cd doses and in the presence of Mn. Thus, damage to the root and leaf tissues of cacao caused by Cd uptake from contaminated soils can be attenuated or mitigated by the presence of high Mn doses in soil.

Cadmium exposure dysregulates purine metabolism and homeostasis across the gut-liver axis in a mouse model

Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.

Blocked erythroid differentiation and delayed enucleation of erythroblasts may contribute to murine embryonic toxicity upon exposure to low dose of cadmium

Epidemiological and experimental studies have demonstrated the association of spontaneous abortion or embryonic atrophy with heavy metals, including some well-known anemia inducers, such as cadmium (Cd). However, the direct adverse effect of Cd on embryos without inducing maternal anemia remains unclear. In this study, we treated mice with a low dose of Cd before and after mating to minimize Cd-induced maternal anemia. Although most embryos developed normally, embryonic atrophy was still observed in a small percentage of embryos from Cd-exposed pregnant mice. Compared to the embryos from the control pregnant mice, a complete blockage of erythroid differentiation was observed in the atrophic embryos but no obvious alteration of erythroid differentiation in the non-atrophic embryos, respectively. Moreover, our results suggested delayed enucleation of erythroblasts in these non-atrophic embryos. Mechanically, the inhibited iron transport from the placenta to the fetus together with the increased iron export in the fetal livers might contribute to embryonic atrophy and delayed enucleation of erythroblasts upon Cd exposure. Our data may provide new insights into the embryonic toxicity of low-dose Cd.

Co-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development

Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.

APP/PS1 Gene-Environmental Cadmium Interaction Aggravates the Progression of Alzheimer's Disease in Mice via the Blood-Brain Barrier, Amyloid-β, and Inflammation.

There is limited information about gene-environment interaction on the occurrence and the progression of Alzheimer's disease. To explore the effect of environmental low-dose cadmium (Cd) exposure on the progress of Alzheimer's disease and the underlining mechanism. We administered 1 mg/L, 10 mg/L cadmium chloride (treated groups), and water (control group) to C57BL/6J and APP/PS1 mice through drinking water, from one week before mating, until the offspring were sacrificed at 6 months of age. The behaviors, Cd level, blood-brain barrier (BBB) leakage, Aβ1-42 deposition, and inflammation expression were evaluated in these mice. Mice of both genotypes had similar blood Cd levels after exposure to the same dose of Cd. The toxic effects of Cd on the two genotypes differed little in terms of neuronal histomorphology and BBB permeability. Cd caused a series of pathological morphological changes in the mouse brains and more fluorescent dye leakage at higher doses. Furthermore, the APP/PS1 mice had more severe damage than the C57BL/6J mice, based on the following five criteria. They were increasing anxiety-like behavior and chaos movement, spatial reference memory damage, Aβ plaque deposition in mouse brains, increasing microglia expression in the brain, and IL-6 higher expression in the cortex and in the serum. Low-dose Cd exposure for 6 months increases Aβ plaque deposition and BBB permeability, exacerbates inflammatory responses, and activates microglia, in APP/PS1 mice. APP/PS1 gene-environmental Cd interaction aggravates the progression of Alzheimer's disease in mice.

Induction of antioxidant defenses by a low-dose cadmium priming alleviates heat stress in pigeon pea

Global warming has a devastating effect on the growth and productivity of plants. Pigeon pea, the second most important legume crop with high nutritional value, is at high risk due to high temperature exposure. Priming is an innovative agronomical application that can be used as a strategy to minimize the detrimental effects of any kind of stresses. In this study, we investigated how low dose of cadmium priming alleviates heat stress (HS) in pigeon pea seedlings. The results demonstrated that low dose of cadmium priming induced the expression of antioxidant systems and maintain a redox homeostasis. An enhanced level of antioxidant glutathione, and antioxidative enzymes (SOD, APX, and GR) were observed in Cd+HS leaf (40 μM Cd priming followed by exposure to HS, 42°C) as compared to the HS leaf. Moreover, a reduction in hydrogen peroxide (H2O2) and oxidized glutathione (GSSG) content was also noticed in Cd+HS leaf. The GSH/GSSG ratio, which was indicative of the redox state in the plant system, was also high in Cd+HS leaf as compared to HS leaf. Thus, the priming of pigeon pea seeds with low dose Cd alleviates HS by elevating antioxidant defenses, ultimately protecting pigeon pea seedlings against HS.

Hormesis in the heavy metal accumulator plant Tillandsia ionantha under Cd exposure: Frequency and function of different biomarkers

Cadmium is one of the most biotoxic substances among all heavy metals, but an increasing number of studies indicate that low-dose Cd can induce hormesis in some plants. However, the frequency of hormesis in various biomarkers (molecular, resistance, and damage markers) and their associated function in hormesis-generation are poorly understood. In this study, the heavy metal accumulator plant Tillandsia ionantha Planch. was exposed to 5 mM CdCl2 with 6 different time periods. The trends of 18 biomarkers after Cd exposure were detected. The percentage for all non-monophasic responses based on dose-response modeling was higher (50 %), in which seven (38.89 %) biomarkers showed hormesis, indicating that hormesis effect can commonly occur in this plant. However, the occurrence frequency of hormesis in different types of biomarkers was different. Six Cd resistance genes, glutathione (GSH) among 6 resistance markers, and 0 damage markers showed hormesis. Factor analysis further showed that the 6 Cd resistance genes and GSH were positively intercorrelated in the first principal component. Therefore, heavy metal resistance genes and GSH may play an important role in the generation of hormesis. Our experiment shows that time-dependent non-monophasic responses, including hormesis, are activated by considerably high concentrations of Cd, presenting a strategy to cope with and potentially reduce the anticipated damage as the dose of stress increases over time.

Proteomic analysis reveals differential responsive mechanisms in Solanum nigrum exposed to low and high dose of cadmium

Cadmium (Cd) contamination is becoming a widespread environmental problem. However, the differential responsive mechanisms of Cd hyperaccumulator Solanum nigrum to low or high dose of Cd are not well documented. In this study, phenotypic and physiological analysis firstly suggested that the seedlings of S. nigrum showed slight leaf chlorosis symptoms under 25 μM Cd and severe inhibition on growth and photosynthesis under 100 μM Cd. Further proteomic analysis identified 105 differentially expressed proteins (DEPs) in the Cd-treated leaves. Under low dose of Cd stress, 47 DEPs are mainly involved in primary metabolic processes, while under high dose of Cd stress, 92 DEPs are mainly involved in photosynthesis, energy metabolism, production of phytochelatin and reactive oxygen species (ROS). Protein-protein interaction (PPI) network analysis of DEPs support above differential responses in the leaves of S. nigrum to low and high dose of Cd treatments. This work provides the differential responsive mechanisms in S. nigrum to low and high dose of Cd, and the theoretical foundation for the application of hyperaccumulating plants in the phytoremediation of Cd-contaminated soils.

Cadmium Activates EGFR/STAT5 Signaling to Overcome Calcium Chelation and Promote Epithelial to Mesenchymal Transition.

Cadmium (Cd) is a heavy metal found in cigarette smoke, as well as in air and drinking water due to agricultural and industrial activities, and it poses a health risk to the general population. Prolonged low-dose Cd exposure via inhalation or ingestion causes lung and kidney cancers in humans and in animal models. While high doses of Cd exposure are correlated with the occupational setting and are cytotoxic, low doses of Cd are mainly correlated with exposure in the general population and induce carcinogenesis. The mechanism by which Cd-exposed cells overcome calcium chelation and induce malignant transformation remains unclear. This study examines how cells exposed to low doses of Cd survive loss of E-cadherin cell-cell adhesion via activation of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 5 (STAT5), which work to upregulate genes associated with survival and proliferation. To demonstrate the role of Cd in EGFR/STAT5 activation, we exposed two epithelial cell lines, BEAS-2B and HEK293, to two different doses (0.4 µM and 1.6 µM) of Cadmium chloride hemipentahydrate (CdCl2·2.5H2O) that are environmentally relevant to levels of Cd found in food and cigarettes for 24 h (hours) and 9 weeks (wks). When comparing cells treated with Cd with control cells, the Cd treated cells exhibited faster proliferation; therefore, we studied activation of EGFR via the STAT5 pathway using immunofluorescence (IF) for protein expression and localization and, in addition, RT-qPCR to examine changes in EGFR/STAT5 inducible genes. Our results showed an increase in EGFR and phosphorylated EGFR (p-EGFR) protein, with 1.6 µM of Cadmium having the highest expression at both 24-hour (hr) and 9-week (wk) exposures. Moreover, the IF analysis also demonstrated an increase of STAT5 and phosphorylated STAT5 (pSTAT5) in both short-term and long-term exposure, with 0.4 µM having the highest expression at 24 h. Finally, via Western blot analysis, we showed that there was a dose-dependent decrease in E-cadherin protein expression and increased N-cadherin in cells treated with low doses of Cd. These data demonstrate that epithelial cells can overcome Cd-mediated toxicity via activation of EGFR pathway to induce cell proliferation and survival and promote epithelial to mesenchymal transition.

Radıometrıc Measurements in of Ladybird (Berberis Thunbergii), Bowood (Buxus Sempervirens Rotundifolia) and Gold Tassel (Euonymus Japonica Var. Aurea) Under Cadmıum and Zınc Stress

In this study, the effect of Cd and Zn application on the activity concentration and transfer factors in the Ladybird, Boxwood, and Gold Tassel leaves was investigated using gamma-ray spectrometry. The mean concentrations (in Bq kg-1) of radionuclides in the studied soil samples were found to be 289.40±32.47 for 238U, 241.76±27.47 for 232Th, 783.63±83.46 for 40K, and 31.44±5.63 for R 137Cs while the respective values in the studied species were 168.6±20.1- 288.8±34.5, 145.9±19.1-250.3±32.4, 434.6±52.2-828.4±99.4, and 16.1±1.8-28.3±3.3. The activity concentrations were found to be at the lowest in the control group and 400 µM Zn for all three species, and at the highest level at 25 µM Cd in general. The order of radionuclides by the highest activity concentrations was 40K&gt;238Uz232Th&gt;137C, whereas the order of species was Gold Tassel&gt;Boxwood&gt;Ladybird. TF (232U, 232Th, 40K, and 137Cs) values were found to be between 0.583 and 0.998, between 0.604 and 1.036, between 0.555 and 1.057, and between 0.513 and 0.899. And also, while the order of species by the activity concentration was Gold Tassel&gt;Boxwood&gt;Ladybird the order of species by the TF values was Boxwood&gt;Gold Tassel&gt;Ladybird. In conclusion, plants’ radionuclide activity concentrations were found to be at the highest level in 25 µM Cd group and at the lowest level in the control group. Given all the data, it can be stated that a low dose of Cd was effective on the radioactivity concentrations and Gold Tassel could be used as the indicator plant in radiation pollution.

Anchoring of Nanocomposites Based on Novel Metal Nanocomplexes/Nanocarbonaceous Surfaces and Assessing Their In Vivo Anticancer Effects on Ehrlich Ascites Tumor.

Nanotechnology is the study of materials' unique properties at the nanoscale. Nanomedicine is the application of nanotechnology in medicine, which has been utilized to treat some common diseases, such as cancer. The aim of the present work is to synthesize the cadmium (Cd) nanocomplex using paracetamol as a ligand with a molar ratio of 1:2 M/L that was characterized by different physicochemical methods and to explore the effect of the synthesized Cd nanocomplex on the immune system and the redox status of the body and their anticancer effects on Ehrlich ascites carcinoma (EAC) induced in mice. Eighty female albino mice were separated into Group I: control; Group II: EAC; Group III: EAC treated with a low-dose Cd nanocomplex; and Group IV: EAC treated with a high-dose Cd nanocomplex. Interleukin-6 (IL-6), NLR family pyrin domain containing 3 (NLRP3), and 8-hydroxy 2-deoxyguanosine (8-OHdG) levels were assessed by enzyme-linked immunosorbent assay (ELISA). Peroxynitrite level and glutathione peroxidase activity were assessed by spectrophotometry. NRF2 mRNA expression, cadmium content, and liver and renal toxicity were estimated. Results: There was a significant increase in IL-6, NLRP3, 8-OHdG, peroxynitrite, and NRF2 mRNA expressions and in the glutathione peroxidase activity in EAC treated with low- and high-dose Cd nanocomplexes. However, the EAC treated with high-dose Cd nanocomplex group showed significant liver and renal toxicity. Conclusion: Cadmium nanocomplex has anticancer effects on EAC induced in mice via its effects on the immune system and redox status as well as pyroptosis and epigenetic instability of the body, while high doses of Cd nanocomplex can cause liver and renal toxicity.

Cardiac Development in the Presence of Cadmium: An in Vitro Study Using Human Embryonic Stem Cells and Cardiac Organoids.

Exposure to cadmium (Cd) is associated with cardiovascular diseases. Maternal Cd exposure is a significant risk factor for congenital heart disease. However, mechanisms of Cd on developmental cardiotoxicity are not well defined. We evaluated the effects of Cd on the different stages (mesoderm, cardiac induction, cardiac function) of cardiac development using an early embryo development in vitro model and two- or three-dimensional (2- or 3D) cardiomyocyte and cardiac organoid formation models mimicking early cardiac development. Embryonic stem cells (ESCs) form 3D aggregates, called embryoid bodies, that recapitulate events involved with early embryogenesis (e.g., germ layer formation). This model was used for early germ layer formation and signaling pathway identification. The 2D cardiomyocyte differentiation from the human ESCs model was used to explore the effects of Cd exposure on cardiomyocyte formation and to model mesoderm differentiation and cardiac induction, allowing us to explore different developmental windows of Cd toxicity. The 3D cardiac organoid model was used in evaluating the effects of Cd exposure on contractility and cardiac development. Cd (; ) lowered the differentiation of embryoid bodies to mesoderm via suppression of -signaling pathways. During early mesoderm induction, the mesoderm-associated transcription factors MESP1 and EOMES showed a transient up-regulation, which decreased later in the cardiac induction stage. Cd () lowered mesoderm formation and cardiac induction through suppression of the transcription factors and mesoderm marker genes HAND1, SNAI2, HOPX, and the cardiac-specific genes NKX2-5, GATA4, troponin T, and . In addition, Cd-induced histone modifications for both gene activation (H3K4me3) and repression (H3K27me3), which play vital roles in regulating mesoderm commitment markers. The effects of Cd inhibition on cardiomyocyte differentiation were confirmed in 3D cardiac organoids. In conclusion, using a human ESC-derived 2D/3D in vitro differentiation model system and cardiac organoids, we demonstrated that low-dose Cd suppressed mesoderm formation through mesoderm gene histone modification, thus inhibiting cardiomyocyte differentiation and cardiac induction. The studies provide valuable insights into cellular events and molecular mechanisms associated with Cd-induced congenital heart disease. https://doi.org/10.1289/EHP11208.

Cerebellar injury induced by cadmium via disrupting the heat-shock response.

Cadmium (Cd) is a food contaminant that poses serious threats to animal health, including birds. It is also an air pollutant with well-known neurotoxic effects on humans. However, knowledge on the neurotoxic effects of chronic Cd exposure on chicken is limited. Thus, this study assessed the neurotoxic effects of chronic Cd on chicken cerebellum. Chicks were exposed to 0 (control), 35 (low), and 70 (high) mg/kg of Cd for 90days, and the expression of genes related to the heat-shock response was investigated. The chickens showed clinical symptoms of ataxia, and histopathology revealed that Cd exposure decreased the number of Purkinje cells and induced degeneration of Purkinje cells with pyknosis, and some dendrites were missing. Moreover, Cd exposure increased the expression of heat-shock factors, HSF1, HSF2, and HSF3, and heat-shock proteins, HSP60, HSP70, HSP90, and HSP110. These changes indicate that HSPs improve the tolerance of the cerebellum to Cd. Conversely, the expressions of HSP10, HSP25, and HSP40 were decreased significantly, which indicated that Cd inhibits the expression of small heat-shock proteins. However, HSP27 and HSP47 were upregulated following low-dose Cd exposure, but downregulated under high-dose Cd exposure. This work sheds light on the toxic effects of Cd on the cerebellum, and it may provide evidence for health risks posed by Cd. Additionally, this work also identified a novel target of Cd exposure in that Cd induces cerebellar injury by disrupting the heat-shock response. Cd can be absorbed into chicken's cerebellum through the food chain, which eventually caused cerebellar injury. This study provided a new insight that chronic Cd-induced neurotoxicity in the cerebellum is associated with alterations in heat-shock response-related genes, which indicated that Cd through disturbing heat-shock response induced cerebellar injury.

White adipose tissue as a target for cadmium toxicity.

Cadmium (Cd) is a widespread heavy metal known as a toxic environmental pollutant. Cd exposure is threatening due to its bioaccumulation trait in living systems that exceeds 35 years without a beneficial biological role. Acute exposure to high Cd doses was reported to impact adipose tissue (AT) function adversely. The main aim of this study is to investigate the effect of low-dose chronic Cd exposure on the genes involved in adipose tissue (AT) functions. Adult male Sprague-Dawley rats were exposed to a low Cd dose (15 mg/kg B.W./day) for 10 weeks. Then, three AT depots-subcutaneous AT (SUB-AT), abdominal AT (AB-AT), and retroperitoneal AT (REtrop-AT) were excised for Cd accumulation measures and gene expression analysis. Adiponectin and leptin gene expression levels were investigated as markers for adipocytes function and homeostasis. Our results showed that Cd accumulated in all the tested adipose depots, but SUB-AT was found to be the depot to most accumulate Cd. Also, it was exhibited that chronic exposure to low Cd doses altered the gene expression of adipocytokines. The levels of adiponectin and leptin mRNA expression were downregulated in all tested AT-depots after Cd exposure. The significant adverse effect on SUB-AT compared to other depots indicates different responses based on AT depots location toward Cd exposure. Collectively, these results suggest a toxic effect of Cd that influenced adipocyte function.