Cadmium Co-exposure Research Articles

Obesogenic diet-induced insulin-resistant rats develop neurobehavioral and memory deficits following bisphenol-A and cadmium co-exposure

Objectives Obesogenic high-fat diets (HFD) have been widely implicated in the etiology of dementia-related neuropathologies through the disruption of brain insulin signaling. Likewise, exposure to environmental toxicants has been associated with various neurodegenerative symptoms attributed to their oxidative stress-mediated neurotoxicity. Thus, this study aims to investigate the effects of exposure to the environmental toxicants, bisphenol-A (BPA) and cadmium (Cd), on the exploratory instinct and spatial awareness memory of HFD-induced insulin-resistant adult Wistar rats. Material and Methods Twenty-five adult Wistar rats were randomly assigned to five groups (A–E; n = 5) and treated as follows: A: normal saline; B: 40 mg/kg.bw CdCl2+HFD+Suc; C: 40 mg/kg.bw BPA+HFD+Suc; D: 40 mg/kg.bw BPA+ 40 mg/kg.bw CdCl2+HFD+Suc; E: HFD+Suc, orally for 56 days. Rats were subjected to the Y-maze behavioral test for spatial awareness and learning memory, and the respective trials were recorded as measures of short-term memory and spatial awareness. On the last day of the experiment, brains were excised, the hippocampus was dissected from each group, and samples were processed for H&E histological investigation. Results Results from this study revealed that BPA and Cd impaired exploratory instincts and spatial awareness of insulin-resistant rats by significantly reducing their exploration of the Y-maze. The hippocampus of exposed rats also revealed neurodegenerative-like changes in histoarchitectural studies with extensive nuclear condensation. Conclusion Histomorphological and behavioral evidence from this study suggests that exposure to oxidative stress-inducing and insulin-signaling perturbing chemicals cause deficits in cognitive and short-term memory.

Coenzyme Q10 Attenuates Kidney Injury Induced by Titanium Dioxide Nanoparticles and Cadmium Co-exposure in Rats.

This study examined the possible defensive role of coenzyme Q10 (CQ10) against the impact of cadmium (Cd) and titanium dioxide nanoparticle (TNP) exposure on rat kidneys. Distilled water (1mL/rat), corn oil (1mL/rat), 10mg CQ10/kg b.wt, 50mg TNP/kg b.wt, 5mg Cd/kg b.wt, TNP + Cd, or TNP + Cd + CQ10 was administered orally to seven groups of 70 male Sprague Dawley rats for 60days. The findings demonstrated that TNP and/or Cd exposure considerably raised serum levels of several renal damage products, disturbed electrolyte balance including sodium, potassium, and calcium, decreased antioxidant enzyme concentration in the kidneys, and elevated malondialdehyde. In addition, rats exposed to TNP and/or Cd had significantly higher levels of renal titanium and Cd. In addition, rats exposed to TNP and/or Cd showed significant histopathological lesions and collagen deposition as revealed by H and E and Masson trichrome staining, respectively. The kidneys were severely damaged by the combined effects of TNP and Cd, although CQ10 greatly mitigated these effects. According to the study, exposure to TNP and Cd can damage the kidneys' function and structure, especially when combined. However, CQ10 can protect against TNP and Cd's nephrotoxic effects.

Toxicity of Polystyrene Microplastics with Cadmium on the Digestive System of Rana zhenhaiensis Tadpoles.

Microplastics pollution in freshwater systems is attracting increasing attention. However, our knowledge of its combined toxicity with heavy metals is scarce. In this study, Rana zhenhaiensis was used as the model animal to study the combined poisoning mechanism of cadmium or microplastics on the digestive systems of tadpoles in freshwater. Results showed that the exposure to cadmium and polystyrene increased the mortality and metamorphosis rate of R. zhenhaiensis tadpoles, and delayed their growth and development. Cadmium was detected in the livers and intestines, while polystyrene mainly accumulated in the gills and intestines of tadpoles. The individual exposure of cadmium or polystyrene can cause pathological damage to liver tissue, induce oxidative stress in liver, and change gene expression. Cadmium co-exposure with polystyrene can reduce the cadmium accumulation in the liver. While polystyrene can slightly increase cadmium accumulation in the intestine. Exposure to cadmium and polystyrene altered the abundance and community structure of intestinal microbiota, and polystyrene increased the dysregulation of the gut microbiome. In this study, the combined exposure of microplastics and cadmium had a negative impact on R. zhenhaiensis tadpoles, but the introduction of microplastics on the toxicity of cadmium on the tadpoles needs further investigation, due to the different characteristics of microplastics.

Comparative mitochondrial proteomic: PGAM5-mediated necroptosis through excessive mitophagy in sheep livers under molybdenum and cadmium co-exposure

Accumulation of excessive molybdenum (Mo) and cadmium (Cd) in the environment poses detrimental effects on organisms. The precise mechanisms of hepatotoxicity that are involved with mitochondria, resulting from the co-exposure to Mo and Cd, remain poorly understood and elusive. To fill the gap, a total of 24 sheep were stratified into two groups: control group and Mo + Cd group (45 mg Mo·kg⁻¹·B.W. and 1 mg Cd·kg⁻¹·B.W.). Results showed that exposure to Mo and Cd adversely co-induced the liver function related biochemical marker alterations in serum, histopathological abnormalities, mitochondrial ultrastructure damage and oxidative stress in the livers of sheep. Sequencing results from isolated mitochondria indicated that a total of approximately 4788 mitochondria-localized proteins were identified, of which 360 exhibited significant differential expression. GO and KEGG database analysis demonstrated excessive Mo and Cd primarily induced hepatotoxicity by affecting mitochondria-mediated oxidation-reduction processes, single-organism metabolic processes, and enhancing the TNF signaling pathway. Mo and Cd co-exposure increased the levels of mitophagy- and necroptosis- related factors regulated by PGAM5 in the livers. Consistently, our findings highlight the co-exposure of Mo and Cd induced necroptosis triggered by PGAM5-mediated mitophagy, which offers valuable insights into the toxicological mechanisms underlying the combined effects of Mo and Cd.

Effects of Decabromodiphenyl Ethane and Cadmium Coexposure on Their Bioaccumulation, Oxidative Stress, Root Metabolism, and Rhizosphere Soil Microorganisms in a Soil-Rice System.

Decabromodiphenyl ethane (DBDPE) and cadmium (Cd) are typical pollutants in e-waste, seriously threatening crop growth. This study investigated the bioaccumulation and toxicity mechanisms of DBDPE and Cd in a soil-rice system. The results showed that 50 mg/kg DBDPE could reduce the level of accumulation of Cd in rice roots. DBDPE and Cd induced the antioxidant system (SOD, POD, and MDA) in rice seedlings. The combined exposure reduced the contents of carbohydrates, lipids, amino acids, and organic acids. Phenylalanine and phenylpropanoid metabolisms were identified as the key detoxification metabolic pathways under combined exposure. DBDPE and Cd disrupted the functional cycling of carbon and nitrogen in rhizosphere soil, while Gemmatimonadetes, Actinobacteria, and Bacteroidetes were the key bacterial groups responding to DBDPE and Cd stress. This work provides data for the toxicity risk evaluation of DBDPE and Cd combined exposure to food crops.

Co-exposure to Aluminium and Cadmium Mediates Postpartum Maternal Variation in Brain Architecture and Behaviour of Mice; Involvement of Oxido-nitrergic and Cholinergic Mechanisms : Postpartum effects of Aluminium and Cadmium co-exposure in pregnancy.

Most research has not been done on the possible relationship between pregnant women's cross-metal exposures and postpartum neuroendocrine functions. The purpose of this study was to look into how co-exposure to aluminium chloride (AlCl3) and cadmium chloride (CdCl2) affected the neuroendocrine and neurometabolic changes in postpartum mice. A total of 24 adult pregnant female mice were used for the study. Group 1 served as control and received neither AlCl3nor CdCl2 (n=6), group 2 comprised pregnant mice treated with AlCl3 (10mg/kg), group 3 with CdCl2 (1.5mg/kg), group 4 with a combination of AlCl3(10 mg/kg) and CdCl2 (1.5 mg/kg).Oral treatment of animals was done daily from gestation day 7 to gestation day 20. Upon delivery and weaning on postnatal day 21 (PND 21), behavioural assessment was done on the postpartum mice and immediately followed by sacrifice for assessment of histological and neuroendocrine markers. Our findings revealed that the brain-to-body weight ratio was affected and brain oxidative stress was elevated in mice exposed to AlCl3 and CdCl2 during pregnancy. Given the strong association between postpartum hyperactivity, social interaction index, brain catalase and acetylcholinesterase activity, and the brain/body weight ratio, it is plausible that these effects have played a role in the adverse behavioural abnormalities observed in the postpartum maternal mice. Moreover, it was noted that in certain situations, co-exposures to the metals tended to have opposite effects to single metal exposures.

Polystyrene nanoplastics and cadmium co-exposure aggravated cardiomyocyte damage in mice by regulating PANoptosis pathway

Micro/nanoplastics (M/NPs) are the novel contaminants ubiquitous in the environment. Cadmium (Cd), a kind of heavy metal pollutant widely distributed, could potentially co-exist with PS-NPs in the environment. However, their combined effects on cardiomyocyte and its molecular mechanism in mammals remained ambiguous. Here, we examined whether PANoptosis, an emerging and complicated kind of programmed cell death, was involved in PS-NPs and Cd co-exposure-elicited cardiac injury. In this study, 60 male mice were orally subjected to environmentally relevant concentrations of PS-NPs (1 mg/kg) and/or CdCl2 (1.5 mg/kg) for 35 days. As we speculated, PS-NPs and Cd co-exposure affected the expression of pyroptosis(Caspase-1, Cleaved-Caspase-1, GSDMD, N-GSDMD, AIM2, Pyrin, NLRP3, IL-18, IL-1β)-, apoptosis(Caspase-3, Cleaved-Caspase-3, Caspase-8, Cleaved-Caspase-8, Caspase-7, BAX)- and necroptosis (t-RIPK3, p-RIPK3, t-RIPK1, p-RIPK1, t-MLKL, p-MLKL, ZBP1)-related genes and protein, resulting in growth restriction and damaged myocardial microstructure in mice. Notably, the combined effects on Cd and PS-NPs even predominantly aggravated the toxic damage. Intriguingly, we fortuitously discovered PS-NPs and/or Cd exposure facilitated linear ubiquitination of certain proteins in mice myocardium. In summation, this study shed light toward the effects of Cd and PS-NPs on cardiotoxicity, advanced the understanding of myocardial PANoptosis and provided a scientific foundation for further exploration of the combined toxicological effects of PS-NPs and heavy metals.

Single and Combined Aluminium and Cadmium Exposure during Pregnancy Mediate Changes in Cardio Metabolic Indices in Mice

The potential risk of Aluminium and Cadmium co-exposure is high owing to evidence of their co-contamination of several food products. Therefore, the present study investigated effect of single and combined exposures of aluminium and cadmium during pregnancy on cardio metabolic changes in mice. Following delivery and at the end of 78 days postnatal development, it was observed that exposure to Al and Cd during pregnancy altered indices of cardiac function via pathways related to angiotensin, cardiac troponin and oxidative stress signalling which may have impacted directly on the histoarchitectural features of the heart. Comparatively, prenatal exposure to Cd alone impacted more negatively to the heart in relation to exposure to either Al only or co-exposure to Al and Cd.

Role of circPSEN1 in carbon black and cadmium co-exposure induced autophagy-dependent ferroptosis in respiratory epithelial cells

Carbon black and cadmium (Cd) are important components of atmospheric particulate matter and cigarette smoke that are closely associated with the occurrence and development of lung diseases. Carbon black, particularly carbon black nanoparticles (CBNPs), can easily adsorbs metals and cause severe lung damage and even cell death. Therefore, this study aimed to explore the mechanisms underlying the combined toxicity of CBNPs and Cd. We found that the combined exposure to CBNPs and Cd promoted significantly greater autophagosome formation and ferroptosis (increased malonaldehyde (MDA), reactive oxygen species (ROS), and divalent iron ions (Fe2+) levels and altered ferroptosis-related proteins) compared with single exposure in both 16HBE cells (human bronchial epithelioid cells) and mouse lung tissues. The levels of ferroptosis proteins, transferrin receptor protein 1 (TFRC) and glutathione peroxidase 4 (GPX4), were restored by CBNPs-Cd exposure following treatment with a 3-MA inhibitor. Additionally, under CBNPs-Cd exposure, circPSEN1 overexpression inhibited increases in the autophagy proteins microtubule-associated protein 1 light chain 3 (LC3II/I) and sequestosome-1 (P62). Moreover, increases in TFRC and Fe2+, and decreases in GPX4were inhibited. Knockdown of circPSEN1 reversed these effects. circPSEN1 interacts with autophagy-related gene 5 (ATG5) protein and upregulates nuclear receptor coactivator 4 (NCOA4), the co-interacting protein of ATG5, thereby degrading ferritin heavy chain 1 (FTH1) and increasing Fe2+ in 16HBE cells. These results indicated that the combined exposure to CBNPs and Cd promoted the binding of circPSEN1 to ATG5, thereby increasing autophagosome synthesis and ATG5-NCOA4-FTH1 axis activation, ultimately inducing autophagy-dependent ferroptosis in 16HBE cells and mouse lung tissues. This study provides novel insights into the toxic effects of CBNPs and Cd in mixed pollutants.

Lead and cadmium co-exposure modified PC12 viability and ER stress: study from a 3×3 factorial design.

Although exposure to individual metal does exhibit its toxicity, combined exposures provide a more effective representation of the toxic effects of different heavy metal exposures on public health as well as ecosystems. Furthermore, there are few studies on composite exposure to low concentrations of heavy metals, which is more consistent with real-life exposure. The purpose of this study was to explore the neurotoxicity induced by combined exposure to low concentrations of Lead (Pb) and cadmium (Cd) and the potential interaction of their mixture in vitro. PC12 cells were incubation with the corresponding concentration of cadmium chloride and/or lead acetate. Viability of PC12 cells was measured by CCK8 assay after 12, 24 and 48h incubation. Next, We measured the ROS, mitochondrial membrane potential (MMP) and apoptosis produced by different treated cells using ROS assay kit, JC-1 MMP assay kit and annexin V-FITC/propidium iodide (PI) apoptosis assay kit, respectively. Expression of proteins related to PI3K/AKT and endoplasmic reticulum (ER) stress in PC12 cells were tested by western blotting. Our study was the first to analyze the interaction between Pb and Cd using a 3 × 3 factorial design approach to observe neurotoxicity. The results showed that the combined exposure of them was more cytotoxic than the single metal. The activation of PI3K/AKT signaling pathway and several parameters related to oxidative stress and ER stress were significantly altered in combined exposure to low concentrations of Pb and Cd compared with the Pb or Cd. Regarding apoptosis and ER stress, a synergistic interaction between Pb and Cd was evident. Moreover, evoked ER stress as a mechanism involved in the apoptosis of PC12 cells by the combined exposure to Pb and Cd. The present study provides a theoretical basis used for the toxicological assessment of metal mixtures induced neurotoxicity of concern in terms of public health, and more effective control measures should be taken for the environmental pollution caused by various mixed heavy metals discharged from industry and agriculture.

2,2',4,4'-Tetrabromodiphenyl ether and cadmium co-exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME-dependent pyroptosis in renal tubular epithelial cells.

We have previously found that a mixture exposure of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand-receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.

Alternations in interleukin-1β and nuclear factor kappa beta activity (NF-kB) in rat liver due to the co-exposure of Cadmium and Arsenic: Protective role of curcumin

Cadmium chloride (Cd) and sodium arsenite (As) are two prominent examples of non-biodegradable substances that accumulate in ecosystems, pose a serious risk to human health and are not biodegradable. Although the toxicity caused by individual use of Cd and As is known, the toxicity of combined use (Cd+As) to mammals is poorly understood. The present study aims to investigate the hepatoprotective effect of curcumin (CUR), a naturally occurring bioactive component isolated from the root stem of Curcuma longa Linn., in preventing liver damage caused by a Cd+As mixture. A group of 30 Sprague-Dawley rats were subjected to intraperitoneal administration of Cd+As (0.44 mg/kg+5.55 mg/kg i.p.) and CUR (100 or 200 mg/kg) for a period of 14 days. The experimental results showed that the animals treated with Cd+As exhibited changes in liver biochemical parameters, inflammation and oxidative stress at the end of the experiment. Administration of CUR significantly reduced inflammation, oxidative stress and lipid peroxidation in the Cd+As plus CUR groups compared to the Cd+As group. Furthermore, histological examination of the liver tissue showed that administration of CUR had led to a significant reduction in the liver damage observed in the Cd+As group. The present study provides scientific evidence for the protective effects of CUR against lipid peroxidation, inflammation, oxidative stress and liver damage induced by Cd+As in the liver of rats. The results of our in vivo experiments were confirmed by those of our molecular modelling studies, which showed that CUR can enhance the diminished antioxidant capacity caused by Cd+As.

Network-based Toxicogenomics Approach to Unraveling the Influence of Lead and Cadmium Mixture on the Development and Progression of Hypertension

Heavy metals, generally characterized by high densities and atomic weights, are ubiquitous in the environment and are a public health concern due to the several health issues they pose to humans. Of all heavy metals, lead and cadmium among others are known to be capable of inducing multiple health effects even at a low rate of exposure. Hypertension (HYP), a major cause of death and a risk factor for other cardiovascular diseases, is known to be caused by both lead and cadmium. While the mechanism underlying the development of HYP induced by independent exposure to lead and cadmium has been well studied, the mechanism underlying the induction and progression of HYP upon lead and cadmium co-exposure remains mildly explored. Hence, this study aimed to elucidate the mechanism using a toxicogenomic approach. The set of genes affected by both heavy metals was identified using the comparative toxicogenomics database (CTD) while HYP targets were retrieved from the Gene Cards database. The shared genes between the heavy metals and the disease were identified and subjected to further analysis. The results of our analysis revealed the signaling pathways that are dysregulated by lead and cadmium co-exposure while oxidative stress, inflammation, and endothelial dysfunction were revealed as processes pertinent to the induction and progression of HYP by lead and cadmium co-exposure. Biomarkers that could be used for prognosis evaluation were also identified. Ultimately, this study supports and advances the growing body of finding on the roles played by lead and cadmium co-exposure in inducing HYP.

Protective Effects of Sodium Para-Aminosalicylic Acid on Lead and Cadmium Co-Exposure in SH-SY5Y Cells.

Combined exposure to lead and cadmium is common in occupational environments. However, the effects of co-exposure to Pb-Cd on neurotoxicity have not been fully clarified. Sodium para-aminosalicylic acid (PAS-Na) has previously been shown to protect neurons from Pb-induced toxicity. This study aimed to investigate the beneficial effect of PAS-Na against co-exposure to Pb-Cd-induced neurodegeneration in SH-SY5Y cells. The MTT assay was used to detect the effects of Pb and Cd alone, or in combination, on SH-SY5Y cell survival. The effects of Pb and Cd alone or in combination on oxidative stress were assessed by reactive oxygen species (ROS) level. Nrf2, the master switch for antioxidant responses, was detected by immunofluorescence. Protein expression levels of PI3K, Akt, p-Akt, Nrf2 and HO-1 were determined by Western blot analysis. MTT assay results established that the survival rate of SH-SY5Y cells was not significantly affected by exposure to 1 μmol/L lead, 0.25 μmol/L cadmium, and 1-fold Pb-Cd mixture (1 μmol/L Pb + 0.25 μmol/L Cd), while 10-fold Pb-Cd combined exposure (10 μmol/L Pb + 2.5 μmol/L Cd) significantly reduced the survival rate of SH-SY5Y cells. Combined Pb-Cd exposure significantly increased intracellular ROS levels, and N-Acetyl-L-cysteine (NAC) treatment in the 10 μmol/L Pb + 2.5 μmol/L Cd group significantly decreased ROS expression levels, attenuating the levels of oxidative stress. Protein expression of PI3K and p-Akt significantly decreased in the 10 μmol/L Pb + 2.5 μmol/L Cd group, while the expression of PI3K and p-Akt protein increased after PAS-Na intervention. Immunofluorescence analysis showed that levels of Nrf2 in the nucleus increased in the 10 μmol/L Pb + 2.5 μmol/L Cd group, along with Nrf2 protein levels, suggesting that Nrf2 was translocated from the cytoplasm into the nucleus upon combined Pb-Cd exposure. In addition, HO-1 protein expression level, a downstream gene product of Nrf2, was increased. In response to NAC intervention, HO-1 protein expression levels significantly decreased. PAS-Na had the same intervention effect as NAC. Combined exposure to Pb-Cd induced oxidative stress and cytotoxicity in SH-SY5Y cells. PAS-Na displayed antagonistic effects on neurodegenerative changes induced by combined Pb-Cd exposure; hence, it may afford a novel treatment modality for exposure to these metals.

Exposure to lead and cadmium is associated with fasting plasma glucose and type 2 diabetes in Chinese adults.

Exposure to lead and cadmium has been associated with type 2 diabetes, but the results are largely inconsistent, and little is known about their joint effect. We aimed to investigate the associations of lead and cadmium co-exposure with fasting plasma glucose (FPG) and type 2 diabetes. The study included 5732 participants aged ≥18years from 16 communities in East China. Blood levels of lead and cadmium were determined using graphite furnace atomic absorption spectrometry. Multivariable linear and logistic regression models were performed to evaluate the associations of lead and cadmium alone or in combination with FPG and diabetes. The median (interquartile range) values of blood lead and cadmium were 40.0 (26.8-57.9) and 1.70 (0.56-3.60)μg/L, respectively. After adjustment for potential confounders, blood lead levels were positively associated with FPG (difference comparing extreme lead quartiles=0.11 [95% CI: 0.03, 0.20]mmol/L) and prevalent diabetes (odds ratio [OR]=1.35 [95% CI: 1.03, 1.78]). The association between lead and diabetes was observed among participants with high cadmium, but not among those with low cadmium (P for interaction=0.03). In the joint analysis, compared with participants with low levels of blood lead and cadmium, participants with high levels of two metals had a 0.16 (95% CI: 0.07, 0.25) mmol/L increase in FPG and a 51% (OR=1.51, 95% CI: 1.15, 1.99) increase in odds of diabetes. Our findings suggest that lead and cadmium co-exposure is significantly associated with elevated FPG and type 2 diabetes in the general population.

Associations of blood lead and cadmium co-exposure and hepatic dysfunction: A cross-sectional study among Chinese adults aged 18 and older

Associations of blood lead and cadmium co-exposure and hepatic dysfunction: A cross-sectional study among Chinese adults aged 18 and older

Molybdenum and cadmium co-exposure promotes M1 macrophage polarization through oxidative stress-mediated inflammatory response and induces pulmonary fibrosis in Shaoxing ducks (Anas platyrhyncha).

High molybdenum (Mo) and cadmium (Cd) are harmful to the body, but pulmonary toxicity induced by Mo and Cd co-exposure is unknown. To assess the combined impacts of Mo and Cd on fibrosis through M1 polarization in the lung of ducks, 80 healthy 8-day-old Shaoxing ducks (Anas platyrhyncha) were randomly assigned to 4 groups and fed with containing unequal doses of Mo or/and Cd diet. Lung tissues were collected on the 16th week. Results indicated that Mo or/and Cd significantly increased their contents in the lungs, and led to trace elements disorder and histological abnormality, and oxidative stress accompanied by promoting contents of H2 O2 and MDA and decreasing activities of T-SOD, GSH-Px, and CAT, then activated the TLR4/NF-κB/NLRP3 pathway accompanied by upregulating Caspase-1, ASC, IL-18, IL-1β, TLR4, NF-κB, and NLRP3 expression levels, and disrupted M1/M2 balance to divert toward M1, which evoked the TGF-β/Smad2/3-mediated fibrosis by elevating TGF-β1, Smad2, Smad3, COL1A1, α-SMA, and MMP2 expression levels, and decreasing Smad7 and TIMP2 expression levels. The changes of the combined group were most obvious. To sum up, the research demonstrated that Mo or/and Cd may cause macrophages to polarize toward M1 by oxidative stress-mediated the TLR4/NF-κB/NLRP3 pathway, then result in fibrosis through the TGF-β1/Smad2/3 pathway in duck lungs. Mo and Cd may worsen lung damage.

Molybdenum and cadmium co-exposure induces CaMKKβ/AMPK/mTOR pathway mediated-autophagy by subcellular calcium redistribution in duck renal tubular epithelial cells

Excessive molybdenum (Mo) and cadmium (Cd) are toxic environmental pollutants. Our previous research confirmed excessive Mo and Cd co-induced calcium homeostasis disorder and autophagy in duck kidneys, but how calcium ion (Ca2+) regulates autophagy is unclear. The results revealed that the Mo- and/or Cd-induced cytosolic Ca2+ concentration ([Ca2+]c) increase mainly came from intracellular calcium stores. Mo and/or Cd caused mitochondrial Ca2+ content ([Ca2+]mit) and [Ca2+]c increase with endoplasmic reticulum (ER) Ca2+ content ([Ca2+]ER) decrease and upregulated calcium homeostasis-related factor expression levels, but 2-Aminoethoxydiphenyl borate (2-APB) reversed subcellular Ca2+ redistribution. Increased Phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3) activities and inositol 1,4,5-trisphosphate receptor (IP3R) expression level were observed in Mo- and/or Cd-treated cells, which was reversed by the PLC inhibitor U-73122. 2-APB and 1,2-Bis (2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM) addition mitigated [Ca2+]c and autophagy (variations in microtubule-associated protein light chain 3 (LC3), LC3B-II/LC3B-I, autophagy related 5 (ATG5), sequestosome-1(P62), programmed cell death-1 (Beclin-1) and Dynein expression levels, LC3 puncta, autophagosomes and acid vesicle organelles) under Mo and/or Cd treatment, respectively, while thapsigargin (TG) had the opposite impacts. Additionally, the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 reversed the increased CaMKKβ, adenosine 5′-monophosphate-activated protein kinase (AMPK), Beclin-1, and LC3B-II/LC3B-I protein expression levels and reduced mammalian target of rapamycin (mTOR) and P62 protein expression levels in Mo- and/or Cd-exposed cells. Collectively, the results confirmed that [Ca2+]c overload resulted from PLC/IP3/IP3R pathway-mediated ER Ca2+ release, and then activated autophagy by the CaMKKβ/AMPK/mTOR pathway in Mo- and/or Cd-treated duck renal tubular epithelial cells.

Mediating effect of telomere length on relationship between lead and cadmium coexposure and blood glucose

Mediating effect of telomere length on relationship between lead and cadmium coexposure and blood glucose

Transcriptomics-based analysis of co-exposure of cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) indicates mitochondrial dysfunction induces NLRP3 inflammasome and inflammatory cell death in renal tubular epithelial cells

Environmental pollution often releases multiple contaminants resulting in as yet largely uncharacterized additive toxicities. Cadmium (Cd) is a widespread pollutant that induces nephrotoxicity in animal models and humans. However, the combined effect of Cd in causing nephrotoxicity with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a typical congener of polybrominated diphenyl ethers (PBDEs), has not been evaluated and mechanisms are not completely clear. Here, we applied transcriptome sequencing analysis to investigate the combined toxicity of Cd and BDE-47 in the renal tubular epithelial cell lines HKCs. Cd or BDE-47 exposure decreased cell viability in a dose-dependent manner, and exhibited cell swelling and rounding similar to necrosis, which was exacerbated by co-exposure. Transcriptomic analysis revealed 2191, 1331 and 3787 differentially-expressed genes following treatment with Cd, BDE-47 and co-exposure, respectively. Interestingly, functional annotation and enrichment analyses showed involvement of pathways for oxidative stress, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammatory cell death for all three treatments. Examination of indices of mitochondrial function and oxidative stress in HKC cells showed that the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and intracellular calcium ion concentration [Ca2+]i were elevated, while superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) were decreased. The ratio of apoptotic and necrotic cells and intracellular lactate dehydrogenase (LDH) release were increased by Cd or BDE-47 exposure, and was aggravated by co-exposure, and was attenuated by ROS scavenger N-Acetyl-L-cysteine (NAC). NLRP3 inflammasome and pyroptosis pathway-related genes of NLRP3, adaptor molecule apoptosis-associated speck-like protein (ASC), caspase-1, interleukin-18 (IL-18) and IL-1β were elevated, while gasdermin D (GSDMD) was down-regulated, and protein levels of NLRP3, cleaved caspase-1 and cleaved GSDMD were increased, most of which were relieved by NAC. Our data demonstrate that exposure to Cd and BDE-47 induces mitochondrial dysfunction and triggers NLRP3 inflammasome and GSDMD-dependent pyroptosis leading to nephrotoxicity, and co-exposure exacerbates this effect, which could be attenuated by inhibiting ROS. This study provides a further mechanistic understanding of kidney damage, and co-exposure impact is worthy of concern and should be considered to improve the accuracy of environmental health assessment.