Low Doses Of Cadmium Research Articles

Mechanistic role for mTORC1 signaling in profibrotic toxicity of low-dose cadmium

Mechanistic role for mTORC1 signaling in profibrotic toxicity of low-dose cadmium

Low-dose cadmium telluride quantum dots trigger M1 polarization in macrophages through mTOR-mediated transcription factor EB activation

The increasing application of quantum dots (QDs) increases interactions with organisms. The inflammatory imbalance is a significant manifestation of immunotoxicity. Macrophages maintain inflammatory homeostasis. Using macrophages differentiated by phorbol 12-myristate 13-acetate-induced THP-1 cells as models, the study found that low-dose (5 μM) cadmium telluride QDs (CdTe-QDs) hindered monocyte-macrophage differentiation. CD11b is a surface marker of macrophage, and the addition of CdTe-QDs during induction resulted in a decrease in CD11b expression. Moreover, exposure of differentiated THP-1 macrophage (dTHP-1) to 5 μM CdTe-QDs led to the initiation of M1 polarization. This was indicated by the increased surface marker CD86 expression, along with elevated level of NF-κB and IL-1β proteins. The potential mechanisms are being explored. The transcription factor EB (TFEB) plays a significant role in immune regulation and serves as a crucial regulator of the autophagic lysosomal pathway. After exposed to CdTe-QDs, TFEB activation-mediated autophagy and M1 polarization were observed to occur simultaneously in dTHP-1. The mTOR signaling pathway contributed to TFEB activation induced by CdTe-QDs. However, mTOR-independent activation of TFEB failed to promote M1 polarization. These results suggest that mTOR-TFEB is an advantageous target to enhance the biocompatibility of CdTe-QDs.

Involvement of ERK and Oxidative Stress in Airway Exposure to Cadmium Chloride Aggravates Airway Inflammation in Ovalbumin-Induced Asthmatic Mice.

Inhalation represents a significant route of cadmium (Cd) exposure, which is associated with an elevated risk of lung diseases. This research study aims to evaluate the impact of repeated low-dose cadmium inhalation on exacerbating airway inflammation induced by ovalbumin (OVA) in asthma-afflicted mice. Mice were grouped into four categories: control (Ctrl), OVA, cadmium chloride (CdCl2), and OVA + cadmium chloride (OVA + CdCl2). Mice in the OVA group displayed increased airway mucus secretion and peribronchial and airway inflammation characterized by eosinophil cell infiltration, along with elevated levels of Th2 cytokines (IL-4, IL-5, IL-13) in bronchoalveolar lavage fluids (BALFs). These parameters were further exacerbated in the OVA + CdCl2 group. Additionally, the OVA + CdCl2 group exhibited higher levels of the oxidative stress marker malondialdehyde (MDA), greater activity of glutathione peroxidase (GSH-Px), and higher phosphorylation of extracellular regulated kinase (ERK) in lung tissue. Treatment with U0126 (an ERK inhibitor) and α-tocopherol (an antioxidant) in the OVA + CdCl2 group resulted in reduced peribronchial and airway inflammation as well as decreased airway mucus secretion. These findings indicate that CdCl2 exacerbates airway inflammation in OVA-induced allergic asthma mice following airway exposure. ERK and oxidative stress are integral to this process, and the inhibition of these pathways significantly alleviates the adverse effects of CdCl2 on asthma exacerbation.

Low dose cadmium inhibits syndecan-4 expression in glycocalyx of glomerular endothelial cells.

Cadmium (Cd) is one of the most polluting heavy metal in the environment. Cd exposure has been elucidated to cause dysfunction of the glomerular filtration barrier (GFB). However, the underlying mechanism remains unclear. C57BL/6J male mice were administered with 2.28 mg/kg cadmium chloride (CdCl2) dissolved in distilled water by oral gavage for 14 days. The expression of SDC4 in the kidney tissues was detected. Human renal glomerular endothelial cells (HRGECs) were exposed to varying concentrations of CdCl2 for 24 h. The mRNA levels of SDC4, along with matrix metalloproteinase (MMP)-2 and 9, were analyzed by quantitative PCR. Additionally, the protein expression levels of SDC4, MMP-2/9, and both total and phosphorylated forms of Smad2/3 (P-Smad2/3) were detected by western blot. The extravasation rate of fluorescein isothiocyanate-dextran through the Transwell was used to evaluate the permeability of HRGECs. SB431542 was used as an inhibitor of transforming growth factor (TGF)-β signaling pathway to further investigate the role of TGF-β. Cd reduced SDC4 expression in both mouse kidney tissues and HRGECs. In addition, Cd exposure increased permeability and upregulated P-Smad2/3 levels in HRGECs. SB431542 treatment inhibited the phosphorylation of Smad2/3, Cd-induced SDC4 downregulation, and hyperpermeability. MMP-2/9 levels increased by Cd exposure was also blocked by SB431542, demonstrating the involvement of TGF-β/Smad pathway in low-dose Cd-induced SDC4 reduction in HRGECs. Given that SDC4 is an essential component of glycocalyx, protection or repair of endothelial glycocalyx is a potential strategy for preventing or treating kidney diseases associated with environmental Cd exposure.

Low dose cadmium exposure regulates miR-381–ANO1 interaction in airway epithelial cells

Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death worldwide. Cigarette smoke which has approximately 2–3 µg of Cadmium (Cd) per cigarette contributes to the environmental exposure and development and severity of COPD. With the lack of a cadmium elimination mechanism in humans, the contribution of cadmium induced stress to lung epithelial cells remains unclear. Studies on cadmium responsive miRNAs suggest regulation of target genes with an emphasis on the critical role of miRNA–mRNA interaction for cellular homeostasis. Mir-381, the target miRNA in this study is negatively regulated by cadmium in airway epithelial cells. miR-381 is reported to also regulate ANO1 (Anoctamin 1) expression negatively and in this study low dose cadmium exposure to airway epithelial cells was observed to upregulate ANO1 mRNA expression via mir-381 inhibition. ANO1 which is a Ca2+-activated chloride channel has multiple effects on cellular functions such as proliferation, mucus hypersecretion and fibroblast differentiation in inflamed airways in chronic respiratory diseases. In vitro studies with cadmium at a high concentration range of 100–500 µM is reported to activate chloride channel, ANO1. The secretory epithelial cells are regulated by chloride channels like CFTR, ANO1 and SLC26A9. We examined “ever” smokers with COPD (n = 13) lung tissue sections compared to “never” smoker without COPD (n = 9). We found that “ever” smokers with COPD had higher ANO1 expression. Using mir-381 mimic to inhibit ANO1, we demonstrate here that ANO1 expression is significantly (p < 0.001) downregulated in COPD derived airway epithelial cells exposed to cadmium. Exposure to environmental cadmium contributes significantly to ANO1 expression.

Changes in the level of trace elements in the rat brain after exposure to low doses of cadmium

Cadmium is one of the most common toxic elements. Due to its great chemical similarity to calcium, copper and zinc, it can replace them. Food is the main route of cadmium intake into the human body. There are very few studies on the effect of low doses of cadmium on the metabolism of trace elements, so it is of interest to study the effects of exposure to low levels of cadmium in brain tissues.&#x0D; The study aims to evaluate the accumulation of cadmium in the brain of experimental animals and its effect on the level of trace elements.&#x0D; We have divided the animals into four groups (n=10): the first group served as a control, groups two, three and four, received one, ten and 100 micrograms of cadmium per kg of body weight (Cd1, Cd10, Cd100), respectively, for 30, 60 and 90 days. The researchers injected cadmium chloride solution daily through a gastric tube. The content of cadmium, calcium, copper and zinc in the brain was assessed using atomic absorption analysis.&#x0D; The results of this study showed that cadmium chloride intoxication did not lead to metal accumulation in the brain in the Cd1 and Cd10 groups, and the value of cadmium concentration in the Cd100 group did not depend on the time of exposure. The researchers have observed statistically significant changes in zinc and copper concentrations after three months of exposure to cadmium. The zinc content increased depending on the dose, and the copper content decreased.&#x0D; Exposure to cadmium for three months in small doses does not lead to significant accumulation in the brain, but causes an imbalance of essential elements such as calcium, zinc and copper.&#x0D; Ethics. The study was conducted in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experiments or Other Scientific Purposes (ETS No. 123), Directive 2010/63/EC of the European Parliament and of the Council of the European Union dated 09/22/2010 on the protection of animals used for scientific purposes and approved by the Bioethical Commission of the Ufa Research Institute of Occupational Medicine and Human Ecology.

Mechanisms of Cadmium Neurotoxicity

Cadmium is a heavy metal that increasingly contaminates food and drink products. Once ingested, cadmium exerts toxic effects that pose a significant threat to human health. The nervous system is particularly vulnerable to prolonged, low-dose cadmium exposure. This review article provides an overview of cadmium’s primary mechanisms of neurotoxicity. Cadmium gains entry into the nervous system via zinc and calcium transporters, altering the homeostasis for these metal ions. Once within the nervous system, cadmium disrupts mitochondrial respiration by decreasing ATP synthesis and increasing the production of reactive oxygen species. Cadmium also impairs normal neurotransmission by increasing neurotransmitter release asynchronicity and disrupting neurotransmitter signaling proteins. Cadmium furthermore impairs the blood–brain barrier and alters the regulation of glycogen metabolism. Together, these mechanisms represent multiple sites of biochemical perturbation that result in cumulative nervous system damage which can increase the risk for neurological and neurodegenerative disorders. Understanding the way by which cadmium exerts its effects is critical for developing effective treatment and prevention strategies against cadmium-induced neurotoxic insult.

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.

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.

Effects of cadmium exposure during the breeding period on development and reproductive functions in rare minnow (Gobiocypris rarus).

Cadmium is a common reproductive toxin in aquatic systems. Cd exposure of fish species at high concentrations can severely affect the reproductive function of fish. However, the underlying toxicity of cadmium exposure at low concentrations on the reproductive function in parental fish remains unclear. To investigate the impacts of cadmium exposure on reproductive capability, eighty-one male and eighty-one female rare minnows (Gobiocypris rarus) were exposed to cadmium at 0 (control group), 5 and 10μg/L for 28days, and then transferred into clean water to pair spawn. The results showed that cadmium exposure at 5 or 10μg/L for 28days in rare minnows could reduce the success rates of pair spawning in parent rare minnows, lessen no-spawning activities, and prolong the time for first spawning. Furthermore, the mean egg production of the cadmium exposure group increased. The fertility rate of the control group was significantly higher than that of the 5μg/L cadmium exposure group. Anatomical and histological data further revealed that the intensity of atretic vitellogenic follicles significantly increased and spermatozoa vacuolated after cadmium exposure (p < 0.05), but slightly increased the condition factor (CF), and relatively stable gonadosomatic index (GSI) values were also observed in the cadmium exposure groups. These observed results indicated that cadmium exposure at 5 or 10μg/L affected the reproductive activity of paired rare minnow by accumulating Cd in the gonads, and the effect diminished over time. The reproductive risk of low-dose cadmium exposure to fish species remains a cause for concern.

Phenotypic aging mediates the association between blood cadmium and depression: a population-based study.

Depression is a serious public health problem today, especially in middle-aged and older adults. Although the etiology of the disease has not been fully elucidated, environmental factors are increasingly not negligible. Cadmium is widely used in industrial production. The general population may be chronically exposed to low doses of cadmium. This study aimed to investigate the association between blood cadmium and depression and to explore the mediating role of aging indicators in this process. We conducted a cross-sectional study on blood cadmium (N = 7195, age ≥ 20years) using data from the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Aging indicators (biological and phenotypic age) are calculated by combining multiple biochemical and/or functional indicators. To determine the relationship between blood cadmium concentrations and depressive symptoms, we used weighted multivariate logistic regression and restricted cubic spline functions and employed mediation analysis to explore the possible mediating effects of aging indicators in the process. We found a significant positive association between blood cadmium and depression with an odds ratio (OR) and 95% confidence interval (CI): 1.22 (1.04,1.43). Restricted cubic spline analysis found a linear positive association between blood cadmium and depression. In the fully covariate-adjusted model, we found a positive association between blood cadmium and biological age and phenotypic age with β and 95% CI: 1.02 (0.65, 1.39) and 2.35 (1.70, 3.01), respectively. In the mediation analysis, we found that phenotypic age mediated 21.32% of the association between blood cadmium and depression. These results suggest that even exposure to low doses of cadmium can increase the risk of depression and that this process may be mediated by phenotypic aging.

Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction

Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl2) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl2 (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA Gm10532 (lnc-Gm10532) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl2 for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl2-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-Gm10532 increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of Fis1 mRNA. Moreover, lnc-Gm10532 was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.

Multiple Targets of Toxicity in Environmental Exposure to Low-Dose Cadmium.

Dietary assessment reports and population surveillance programs show that chronic exposure to low levels of environmental cadmium (Cd) is inevitable for most people, and adversely impacts the health of children and adults. Based on a risk assessment model that considers an increase in the excretion of β2-microglobulin (β2M) above 300 μg/g creatinine to be the “critical” toxicity endpoint, the tolerable intake level of Cd was set at 0.83 µg/kg body weight/day, and a urinary Cd excretion rate of 5.24 µg/g creatinine was considered to be the toxicity threshold level. The aim of this review is to draw attention to the many other toxicity endpoints that are both clinically relevant and more appropriate to derive Cd exposure limits than a β2M endpoint. In the present review, we focus on a reduction in the glomerular filtration rate and diminished fecundity because chronic exposure to low-dose Cd, reflected by its excretion levels as low as 0.5 µg/g creatinine, have been associated with dose-dependent increases in risk of these pathological symptoms. Some protective effects of the nutritionally essential elements selenium and zinc are highlighted. Cd-induced mitochondrial dysfunction is discussed as a potential mechanism underlying gonadal toxicities and infertility.

Low-dose cadmium exposure promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway

Cadmium (Cd)-induced bone damage may be mediated through activating osteoclastogenesis. However, the underlying mechanism is unknown. The purpose of this study was to explore the effect and possible mechanism of CdCl2-induced osteoclastogenesis in RAW264.7 cells. We found that a low concentration of CdCl2 (0.025 and 0.050 µM) did not affect the viability of RAW264.7 cells, but promoted osteoclastogenesis. A low concentration of CdCl2 increased the mRNA and protein expression of osteoclastogenesis-related genes. TRAP staining and transmission electron microscopy (TEM) also demonstrated that CdCl2 promoted osteoclastogenesis. A low concentration of CdCl2 upregulated the levels of LC3-II and Beclin-1, and decreased p62 expression. TEM showed relatively abundant autophagic vacuoles (autophagosomes) after CdCl2 exposure. A low concentration of CdCl2 downregulated the expression levels of Mtor and p70S6K1, and the relative protein expression ratios of p-mTOR/mTOR and p-p70S6K1/p70S6K1. When cells were treated with the autophagy inhibitor chloroquine (CQ) or mTOR activator MHY1485 combined with CdCl2, the expressions of osteoclastogenesis related-genes were decreased and autophagy was attenuated compared with cells treated with CdCl2 alone. Deficiencies in autophagosomes and osteoclasts were also observed. Taken together, the results indicate that a low concentration of CdCl2 promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway.

Low-Dose Cadmium Potentiates Metabolic Reprogramming Following Early-Life Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) infection causes serious pulmonary disease and death in high-risk infants and elderly. Cadmium (Cd) is a toxic environmental metal contaminant and constantly exposed to humans. Limited information is available on Cd toxicity after early-life respiratory virus infection. In this study, we examined the effects of low-dose Cd exposure following early-life RSV infection on lung metabolism and inflammation using mouse and fibroblast culture models. C57BL/6J mice at 8 days old were exposed to RSV 2 times with a 4-week interval. A subset of RSV-infected mice was subsequently treated with Cd at a low dose in drinking water (RSV infection at infant age [RSVinf]+Cd) for 16 weeks. The results of inflammatory marker analysis showed that the levels of cytokines and chemokines were substantially higher in RSVinf+Cd group than other groups, implying that low-dose Cd following early-life RSV infection enhanced lung inflammation. Moreover, histopathology data showed that inflammatory cells and thickening of the alveolar walls as a profibrotic signature were evident in RSVinf+Cd. The metabolomics data revealed that RSVinf+Cd-caused metabolic disruption in histamine and histidine, vitamin D and urea cycle, and pyrimidine pathway accompanying with mechanistic target of rapamycin complex-1 activation. Taken together, our study demonstrates for the first time that cumulative Cd exposure following early-life RSV infection has a significant impact on subsequent inflammation and lung metabolism. Thus, early-life respiratory infection may reprogram metabolism and potentiate Cd toxicity, enhance inflammation, and cause fibrosis later in life.

Exposure to low-dose cadmium induces testicular ferroptosis

As an environmental pollutant, cadmium (Cd) has been widely reported to induce male infertility due to its gonadotoxicity. However, the specific mechanism of Cd-induced testicular damage remains unclear. We investigated whether Cd causes testicular injury through ferroptosis. Male C57BL/6 J mice were exposed to 0, 0.5, or 5 ppm Cd via drinking water, starting in utero, and continuing through 24 weeks post-weaning. The results showed that Cd accumulated in the testes in a dose-dependent manner. Cd exposure at a concentration of 5 ppm, but not 0.5 ppm, caused a mass loss and detachment of germ cells, as well as a decreased meiotic index and testis weight. Exposure to 5 ppm Cd caused iron accumulation, increased levels of malondialdehyde (MDA) and nitro tyrosine (3-NT), and decreased expression of Nrf2, HO-1 and SOD2. We also found that exposure to 5 ppm Cd significantly decreased the expression of SLC7A11, a marker of ferroptosis in mice, along with the expression of SLC40A1 mRNA and ferritin heavy chain (FTH) protein, whereas there was no obvious change in the mRNA expression of Tfrc, ZIP8, ZIP14, and NCOA4. These findings indicate that 5 ppm Cd exposure increased testicular ferroptosis, which may be attributed to the reduction of stored iron export.

Chronic exposure to low-dose cadmium facilitated nonalcoholic steatohepatitis in mice by suppressing fatty acid desaturation

Exposure to cadmium (Cd), a toxic metal, is epidemiologically linked to nonalcoholic steatohepatitis (NASH) in humans. However, the role of Cd in NASH remains to be fully elucidated. This study employed a novel murine NASH model to investigate the effects of chronic low-dose Cd on hepatic pathology and its underlying mechanisms. NASH is characterized by lipid accumulation, extensive cell death, and persistent inflammation in the liver. We found that treatment with Cd in drinking water (10 mg/L) for 6 or 12 weeks significantly boosted hepatic fat deposition, increased hepatocyte destruction, and amplified inflammatory responses in mice, confirming that low-dose Cd can facilitate NASH development in vivo. Mechanistically, chronic Cd exposure reshaped the hepatic transcriptional landscape, with PPAR-mediated fatty acid metabolic pathways being the most significantly altered. In particular, Cd repressed fatty acid desaturation, leading to the accumulation of saturated fatty acids whose lipotoxicity exacerbated cell death and, consequently, inflammatory activation. In summary, we validated the causal effects of chronic low-dose Cd on NASH in vivo and identified the fatty acid desaturation program as a novel target for Cd to instigate hepatopathological alterations.

Effects of whole-life exposure to low-dose cadmium with post-weaning high-fat diet on offspring testes in a male mouse model

Although several studies have reported testicular impairments caused by cadmium (Cd) or obesity alone, the combined effect of Cd and obesity on the testes and its underlying mechanism remains unclear. We examined the combined effect of whole-life exposure to low-dose Cd started at preconception and post-weaning high-fat diet (HFD) on the testes of offspring mice. At weaning, male offspring parented with and without exposure to low-dose Cd were continued on the same drinking water regimen as their parents and fed with either a normal diet (ND) or HFD for 10 or 24 weeks. Whole-life exposure to Cd resulted in its accumulation in testes, and HFD induced obesity and lipid metabolism disorder. Exposure to Cd or HFD alone significantly decreased Johnsen scores, disrupted testicular structure, and increased germ cell apoptosis at both 10 and 24 weeks. However, co-exposure to Cd and HFD did not induce the toxic effects that were induced by either alone, as revealed by preserved testicular structure and spermatogenesis, lack of significant apoptosis, and increased cell proliferation. Mechanistically, the combined effects of low-dose Cd and HFD consumption were associated with the activation of the JAK/STAT pathway. These findings suggest that co-exposure to low-dose Cd and HFD did not cause Cd- or HFD-induced testicular injury, probably because of the activation of the JAK/STAT pathway to prevent germ cell apoptosis.

Whole life exposure to low dose cadmium alters diet-induced NAFLD

Nonalcoholic fatty liver disease (NAFLD) is a major global public health concern affecting more than 25% of the world's population. Although obesity and diabetes are major risk factors for NAFLD, they cannot account for all cases, indicating the importance of other factors such as environmental exposures. Cadmium (Cd) exposure is implicated in the development of NAFLD; however, the influence of early life, in utero Cd exposure on the development of diet-induced NAFLD is poorly understood. Therefore, we developed an in vivo, multiple-hit model to study the effect of whole-life, low dose Cd exposure on high fat diet (HFD)-induced NAFLD. Adult male and female C57BL/6 J mice fed normal diets (ND) were exposed to 0, 0.5 or 5 ppm Cd-containing drinking water for 14 weeks before breeding. At weaning, offspring were fed ND or HFD and continued on the same drinking water regimen as their parents for 24 weeks. Cd exposure at different concentrations differentially altered HFD-associated adverse health effects, including liver injury. HFD-induced increased body weight, decreased glucose tolerance. Liver injury and lipid deposition were exacerbated by 5 ppm Cd exposure but attenuated by 0.5 ppm Cd exposure. Further, HFD blunted the response of metallothionein, a major Cd detoxification protein, in mice exposed to 5 ppm Cd but enhanced the response in mice exposed to 0.5 ppm Cd, suggesting a possible mechanism for Cd alteration of HFD-induced NAFLD. These results confirm the multi-hit nature of NAFLD and show whole life, low dose Cd exposure alters HFD-induced NAFLD with outcomes dependent on Cd concentration.