Chronic Pb Exposure Research Articles

Mitigating lead-induced osteoporosis: The role of butyrate in gut-bone axis restoration

Lead (Pb) is an environmentally widespread bone toxic pollutant, contributes to the development of osteoporosis. Butyric acid, mainly produced by the fermentation of indigestible dietary fiber by gut microbiota, plays a pivotal role in the maintenance of bone homeostasis. However, the effects of butyric acids on the Pb induced osteoporosis have not yet been elucidated. In this study, our results showed that Pb exposure was negatively related to the abundance of butyric acid, in the Pb-exposed population and Pb-exposed mice. Pb exposure caused gut microbiota disorders, resulting in the decline of butyric acid-producing bacteria, such as Butyrivibrio_crossotus, Clostridium_sp._JN9, and the butyrate-producing enzymes through the acetyl-CoA pathway. Moreover, results from the NHANES data suggested that dietary intake of butyrate was associated with a reduced risk of osteoporosis in lead-burdened populations, particularly among men or participants aged 18–60 years. In addition, butyrate supplementation in mice with chronic Pb exposure improved the bone microarchitectures, repaired intestinal damage, upregulated the proportion of Treg cells. Taken together, these results demonstrated that chronic Pb exposure disturbs the gut-bone axis, which can be restored by butyric acid supplement. Our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced bone toxicity.

Ameliorating effects of Clerodendrum viscosum leaves on lead‐induced hepatotoxicity

AbstractLead (Pb), a common toxicant is ubiquitously present in the environment. Chronic Pb exposure affects almost every organ system of human body including liver. Clerodendrum viscosum is a medicinal plant and its leaves are known to have hepatoprotective, anti‐inflammatory, and anti‐hyperglycemic activities. However, the protective effect of C. viscosum leaves against Pb‐induced hepatotoxicity is yet to be studied. Therefore, this study was designed to assess the protective effect of the aqueous extract of C. viscosum leaf (Cle) against Pb‐induced hepatotoxicity in experimental mice. Pb‐acetate was given to Pb and Pb + Cle groups interperitoneally, and Cle was supplemented to Cle and Pb + Cle groups by oral gavage. Serum biomarkers of liver function—butyrylcholinesterase (BChE), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine transaminase (ALT), antioxidant enzyme activities in hepatic tissue—superoxide dismutase (SOD), reduced glutathione reductase (rGR) and catalase (CAT), levels of transcription factor—nuclear factor erythroid 2‐related factor 2 (Nrf2), and inflammatory marker—interleukin‐6 (IL‐6) were analyzed. Additionally, histological analyses of hepatic tissues of all groups of experimental mice were performed. Pb‐treatment significantly increased ALP, AST, and ALT activities and decreased BChE activity compared to control mice. The antioxidant enzyme (SOD, rGR, and CAT) activities and expression of Nrf2 level were significantly (p < .05) decreased, while IL‐6 level was significantly (p < .05) increased in the hepatic tissue homogenates of Pb‐treated mice compared to the control group. Furthermore, histological examination revealed the disruption of hepatic tissue integrity in Pb‐treated mice. Notably, supplementation of Cle provided significant protection against the changes in the activities of liver function biomarkers and antioxidant enzymes, levels of Nrf2 and IL‐6, and disruption of hepatic tissue by Pb. Taken together the present study suggests that Cle ameliorates the hepatic toxicity caused by Pb.

Chronic Lead Exposure in Adult Mice: Associations with miR-671/CDR1as Regulation, NF-κB Signaling, and Alzheimer's Disease-like Pathology.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

Lead exposure induces autophagy via TLR4/EEF2 in neurons

Chronic lead (Pb) exposure is known to cause neuronal inflammation and autophagy dysfunction. However, the precise mechanism by which Pb exposure triggers neuronal autophagy remains elusive. This study aimed to elucidate the molecular mechanisms underlying Pb-induced neuronal autophagy. Inflammation and autophagy are closely interconnected cellular processes, with Toll-like receptor 4 (TLR4) playing a significant role in the inflammatory response to Pb. We observed that inhibiting TLR4 resulted in increased expression of Eukaryotic elongation factor 2 (EEF2), which regulated cellular autophagy. The rats and HT22 cells were utilized to establish chronic Pb exposure models. Our data reveals that Pb exposure promotes neuronal autophagy, activates TLR4, and increases EEF2 expression in rat hippocampus and HT22 cells. Additionally, inhibiting TLR4 partially reverses the Pb-induced increase in autophagy and the enhanced expression of EEF2. Overexpression of EEF2 partially counteracted the autophagy induced by Pb exposure. These findings suggest that Pb-induced activation of TLR4 may upregulate EEF2 expression, thereby leading to augmented neuronal autophagy and potential neuronal dysfunction.

Chronic Pb exposure impairs learning and memory abilities by inhibiting excitatory projection neuro-circuit of the hippocampus in mice

Lead (Pb) is an environmental neurotoxic metal. Chronic Pb exposure causes behavioral changes in humans and rodents, such as dysfunctional learning and memory. Nevertheless, it is not clear whether Pb exposure disrupts the neural circuit. Thus, here we aim at investigating the effects the chronic Pb exposure on neural-behavioral and neural circuits in mice from prenatal to postnatal day (PND) 63. Pregnant mice and their male offspring were treated with Pb (150 ppm) until postnatal day 63. In this study, several behavior tests and Golgi-Cox staining methods were used to assess spatial memory ability and synaptogenesis. Virus-based tracing systems and immunohistochemistry assays were used to test the relevance of chronic Pb exposure with disrupted neural circuits. The behavioral experiments and Golgi-Cox staining results showed that Pb exposure impaired spatial memory and spine density in mice. The virus tracing results revealed that the Entorhinal cortex (EC) neurons could be directly projected to Cornuammonis 1 (CA1) and Dentate gyrus (DG), forming a critical circuit inhibited, in either a direct or indirect way, by Pb invasion. In addition, excitatory neural input from EC（labeled with CaMKII）to CA1 and DG was significantly attenuated by Pb exposure. In conclusion, our data indicated that Pb significantly impaired the excitatory connections from EC to the hippocampus (CA1 and DG), providing a novel neuro-circuitry basis for Pb neurotoxicity.

Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by COX17

Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ1-42-treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ1-42, and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ1-42-treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.

Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus.

Lead (Pb) is a widespread neurotoxic pollutant. Pb exposure is associated with mood disorders, with no well-established neural mechanisms elucidated. In the present study, we aimed to investigate whether excitatory neurons in the dentate gyrus subregion of the ventral hippocampus (vDG) played a key role in Pb-induced anxiety and depression-like behaviors. C57BL/6 mice were exposed to 100 ppm Pb starting on day 1 of pregnancy until experiments were performed using the offspring. Behavioral studies suggested that chronic Pb exposure triggered anxiety and depression-like behaviors. A combination of electrophysiological, optogenetic, and immunohistochemistry experiments was conducted. Results showed that Pb exposure resulted in excitatory neuronal hyperexcitability in vDG and that the behavioral deficits caused by Pb exposure could be rescued by inhibition of excitatory neuronal activity. Moreover, it was found that the action potential (AP) threshold of excitatory neurons was decreased by electrophysiological recordings. Our study demonstrates a significant role for excitatory neurons in vDG in Pb-induced anxiety and depression-like behaviors in mice, which is likely a result of decreased AP threshold. These outcomes can serve as an important basis for understanding mechanisms of anxiety and depression under environmental Pb exposure and help in the design of therapeutic strategies.

High affinity of β-amyloid proteins to cerebral capillaries: implications in chronic lead exposure-induced neurotoxicity in rats

Lead (Pb) is a known environmental risk factor in the etiology of Alzheimer’s disease (AD). The existing reports suggest that Pb exposure increases beta-amyloid (Aβ) levels in brain tissues and cerebrospinal fluid (CSF) and facilitates the formation of amyloid plaques, which is a pathological hallmark for AD. Pb exposure has long been associated with cerebral vasculature injury. Yet it remained unclear if Pb exposure caused excessive Ab buildup in cerebral vasculature, which may damage the blood–brain barrier and cause abnormal Ab accumulation. This study was designed to investigate the impact of chronic Pb exposure on Aβ accumulation in cerebral capillary and the expression of low-density lipoprotein receptor protein-1 (LRP1), a critical Aβ transporter, in brain capillary and parenchyma. Sprague–Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ40 was infused into the brain via the cannulated internal carotid artery. Data by ELISA showed a strikingly high affinity of Ab to cerebral vasculature, which was approximately 7–14 times higher than that to the parenchymal fractions collected from control brains. Pb exposure further aggravated the Aβ accumulation in cerebral vasculature in a dose-dependent manner. Western blot analyses revealed that Pb exposure decreased LRP1 expression in cortical capillaries and hippocampal parenchyma. Immunohistochemistry (IHC) studies further revealed a disrupted distribution of LRP1 alongside hippocampal vasculature accompanied with a decreased expression in hippocampal neurons by Pb exposure. Taken together, the current study demonstrated that the cerebral vasculature naturally possessed a high affinity to Aβ present in circulating blood. Pb exposure significantly increased Aβ accumulation in cerebral vasculature; such an increased Aβ accumulation was due partly to the diminished expression of LRP1 in response to Pb in tested brain regions. Perceivably, Pb-facilitated Ab aggravation in cerebral vasculature may contribute to Pb-associated amyloid alterations.

Association between Chronic Environmental Lead (Pb) Exposure and Cytokines in Males and Females of Reproductive Age from Kabwe, Zambia.

Lead (Pb) poisoning remains a great public health challenge globally known to induce a wide range of ailments in both children and adults. The current study investigated the association of chronic environmental Pb exposure and immunomodulatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) in adult males and females living in Kabwe, Zambia. The standard human cytokine/chemokine Milliplex assay was used to quantify plasma cytokines from four groups categorized as low (<10 μg/dL) and high (>10 μg/dL) blood lead level (BLL) groups, namely, low BLL female (n = 47; BLL = 3.76 μg/dL), low BLL Male (n = 43; BLL = 4.13 μg/dL), high BLL female (n = 21; BLL = 23.5 μg/dL), and high BLL male (n = 18; BLL = 23.7 μg/dL), respectively. The low BLL group was associated with increased TNF-α levels, and the high BLL group was associated with reduced TNF-α levels in female subjects. No associations between BLL and the levels of IL-8 and TNF-α cytokines were observed in either females or males, respectively. A negative correlation between BLL and TNF-α was found in female subjects, suggesting that an increase in BLL accompanied by a reduction in TNF-α. The reduced levels of circulating TNF-α in female subjects suggest that chronic Pb exposure could predispose females to immune and inflammation-related disorders than their male counterparts. Further studies are recommended to ascertain the impact of chronic Pb exposure on immunomodulatory cytokines, especially in females.

Role of NF-κB in lead exposure-induced activation of astrocytes based on bioinformatics analysis of hippocampal proteomics

Lead (Pb), as a heavy metal, is used in batteries, ceramics, paint, pipes, certain ceramics, e-waste recycling, etc. Chronic Pb exposure can result in the inflammation of the central nervous system, as well as neurobehavioral changes. Both glial cells and neurons are involved in central nervous injury following Pb exposure. However, significant cellular events and their key regulators following Pb exposure remain to be elucidated. In this study, rats were randomly exposed to 250 or 500 mg/L PbAc for 9 weeks. Hippocampal proteomics was performed using isobaric tags for relative absolute quantification. Bioinformatics analysis was used to identify 301 and 267 differentially expressed proteins—which were involved in biological processes, including glial cell activation, neural nucleus development, and mRNA processing—in the low and high Pb exposure groups, respectively. Gene Set Enrichment Analysis showed that astrocyte activation was identified as a significant cellular event occurring in the low- or high-dose Pb exposure group. Subsequently, in vivo and in vitro models of Pb exposure were established to confirm astrocyte activation. As a result, glial fibrillary acidic protein expression in astrocytes was much higher in the Pb exposure group. Moreover, the mRNA expression of neurotoxic reactive astrocyte genes was much higher than that of the control group. The analysis of transcription factors indicated that NF-κB was screened as the top transcription factor, which might regulate astrocyte activation following Pb exposure in the rat hippocampus. The data also showed that the inhibition of NF-κB transcription suppressed astrocyte activation following Pb exposure. Overall, astrocyte activation was one of the significant cellular events following Pb exposure in the rat hippocampus, which was regulated by the NF-κB transcription factor, suggesting that inhibiting astrocyte activation may be a potential target for the prevention of Pb neurotoxicity.

Reduced DNA Glycosylases Expression and Oxidative DNA Damage Induced by Lead

Exposure to lead (Pb) continues to be a significant worldwide problem. Pb is a highly toxic heavy metal affecting several organ systems in the body. There has been reported to have potential genotoxic properties to various cells. However, the underlying mechanisms of lead-induced toxicity are still unknown. The present study aimed to investigate the lead-induced cytotoxicity in human renal proximal tubular epithelial cells and its underlying DNA damage mechanisms. Lead exposure caused DNA damage as demonstrated by increased 8-OHdG/dG ratio in cells even at a relatively normal dose (10μg/dL). Lead also led to producing oxidative stress as characterized by increased intensity of the Reactive Oxygen Species (ROS) indicator. ROS overproduction should be the reason for lead-induced DNA damage. Therefore, the effects of Lead on ROS elimination should be the main reason for lead-induced oxidative stress in human renal proximal tubular epithelial cells. After lead acetate (PbAc) treatment, the cell viability significantly decreased in a dose-dependent manner, and the accumulation of cellular ROS was observed. 8-OHdG levels, a marker of oxidative DNA damage, were significantly increased by both acute and chronic Pb exposure. Interestingly, the mRNA expression of the 8-oxoguanine DNA glycosylase 1 (hOGG1) significantly decreased after acute and chronic exposure. In conclusion, our study provides the first evidence to demonstrate that acute and chronic Pb exposure results in the altered expression of DNA glycosylases genes indicating the impairment of DNA repair pathways and contributing to DNA damage. These findings should be useful for the more comprehensive assessment of the toxic effects of Pb.

Chronic lead exposure exacerbates hepatic glucolipid metabolism disorder and gut microbiota dysbiosis in high-fat-diet mice.

Lead (Pb) and obesity are co-occurring risk factors for metabolic disorders. However, there is still a lack of study on the combined effects of both stressors on metabolism. C57BL/6J mice were exposed to 200mg/L Pb or/and HFD for 24 weeks and were used to investigate the effects and underlying mechanisms of chronic Pb exposure on obese mice. The results showed that Pb significantly increased body weight, visceral obesity, fasting blood glucose levels, and insulin resistance, and aggravated liver damage, hepatic lipid accumulation and steatosis in HFD-fed mice. Further analysis showed that Pb significantly inhibited insulin signaling pathway PI3K/AKT and fatty acid β-oxidation, and accelerated fatty acid synthesis. Moreover, Pb exacerbated HFD-induced disruption of gut microbiota homeostasis, manifested by increased proportions of pathogenic genera such as Desulfovibrio, Alistipes and Helicobacter, and decreased proportions of beneficial microbes Akkermansia and Barnesiella, which were negatively associated with obesity. These results indicated that Pb exposure exacerbated the disruption of liver glucolipid metabolism in HFD mice possibly by disrupting gut microbiota.

OsNRAMP5 Is a Major Transporter for Lead Uptake in Rice.

Lead (Pb) is one of the most toxic metals affecting human health globally. Food is an important source of chronic Pb exposure in humans. How Pb is taken up by rice, a staple food for over half of the global population, remains unknown. In the present study, we investigated the role of OsNRAMP5, a member of the NRAMP (Natural Resistance-Associated Macrophage Protein) transporter family, in Pb uptake by rice roots. Heterologous expression of OsNRAMP5 in yeast increased Pb uptake and sensitivity toward Pb. Knockout of OsNRAMP5 in rice by CRISPR/Cas9 gene editing resulted in significant decreases in root uptake of Pb and accumulation in rice shoots. The maximum influx velocity (Vmax) for Pb uptake of the knockout mutants was 70% lower than that of wild-type plants. When grown in Pb-contaminated paddy soil, OsNRAMP5 knockout mutants accumulated approximately 50 and 70% lower Pb concentrations in the grain and straw, respectively, than the wild type. OsNRAMP5 expression in rice roots was not affected by Pb exposure. These results indicate that OsNRAMP5 is a major transporter for Pb uptake in rice, in addition to its role in the uptake of manganese and cadmium. This study provides a mechanistic understanding of Pb uptake in rice plants and a potential strategy to limit Pb accumulation in rice grains.

NLRP3 activation in microglia contributes to learning and memory impairment induced by chronic lead exposure in mice.

Lead (Pb)-induced microglial activation and neuroinflammation has been considered as one of the main pathological events of Pb neurotoxicity. The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. However, the relationship between chronic Pb exposure and neurogenic NLRP3 inflammasome is unclear. Therefore, the aim of this study was to characterize the role of NLRP3 inflammasome activation during the chronic Pb exposure using in vitro and in vivo models. Our results showed that chronic Pb exposure induce learning and memory impairment in mice, mainly related to the activation of microglia and NLRP3 inflammasome. This phenomenon was reversed in mice by treating with the NLRP3 inhibitor MCC950 and using NLRP3-/- mice. In addition, Pb caused the activation of NLRP3 inflammasome, the production of mitochondrial ROS (mtROS), and mitochondrial Ca2+ overload in BV2 cells. Amelioration of mtROS abolished Pb-induced NLRP3 inflammasome activation. Moreover, after regulation of Ca2+ redistribution, mtROS and NLRP3 inflammasome activation was restored. In conclusion, NLRP3 inflammasome activation in microglia plays a vital role in Pb neurotoxicity, by a novel mechanism of enhancing mtROS production and Ca2+ redistribution.

High lead exposure and clinical signs of toxicosis in wild Nile crocodiles (Crocodylus niloticus) from a World Heritage site: Lake St Lucia estuarine system, South Africa.

Lead (Pb) exposure is a widespread wildlife conservation threat, but impacts on reptile populations remain poorly documented. In this study, we examined Pb exposure and accumulation in a wild population of Nile crocodiles (Crocodylus niloticus) at Lake St Lucia, South Africa. Recreational angling has occurred in the area since the 1930s and incidental ingestion of Pb fishing weights has previously been identified as a major source of Pb poisoning in the local crocodile population. In 2019, we sampled blood and tail fat tissues from wild (n=22) and captive (n=3) crocodiles at Lake St Lucia to investigate potential impacts of chronic Pb exposure on crocodilian health. Lead was detected in blood samples of all wild crocodiles, although concentrations varied widely between individuals (86-13,100ngml-1). The incidence of Pb poisoning was higher in male crocodiles, with mean blood lead (BPb) concentrations in males (3780±4690ngml-1) significantly (p<0.001) higher compared to females (266±230ngml-1). Blood Pb concentrations were correlated with concentrations measured in tail fat tissue (n.d - 4175ngg-1 wet wt.). Although most of the crocodiles sampled appeared to be in good physical condition, highly elevated BPb concentrations (>6000ngml-1) were associated with markedly suppressed packed cell volumes (4.6-10.8%) and severe deterioration in tooth condition. These findings suggest that anaemia and tooth loss may be clinical signs of long-term environmental exposure to Pb. Although previously undocumented in crocodilians, these symptoms are consistent with Pb poisoning observed in birds and mammals, and suggest that crocodilians may be more susceptible to the long-term toxic effects of Pb than previously thought. In light of these findings, we suggest that the impact of accumulated Pb on crocodilian fitness, reproduction and mortality requires urgent attention.

Association between lead exposure and DNA damage (genotoxicity): systematic review and meta-analysis

Studies suggest that chronic lead (Pb) exposure may induce deoxyribonucleic acid (DNA) damage. However, there is no synthesised evidence in this regard. We systematically reviewed existing literature and synthesised evidence on the association between chronic Pb exposure and markers of genotoxicity. Observational studies reporting biomarkers of DNA damage among occupationally Pb-exposed and unexposed controls were systematically searched from PubMed, Scopus and Embase databases from inception to January 2022. The markers included were micronucleus frequency (MN), chromosomal aberrations, comet assay, and 8-hydroxy-deoxyguanosine. During the execution of thisreview, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Mean differences in the biological markers of DNA damage between Pb-exposed and control groups were pooled using the random-effects model. The heterogeneity was assessed using the Cochran-Q test and I2 statistic. The review included forty-five studies comparing markers of DNA damage between Pb-exposed and unexposed. The primary studies utilised buccal and/or peripheral leukocytes for evaluating the DNA damage. The pooled quantitative results revealed significantly higher DNA damage characterised by increased levels of MN and SCE frequency, chromosomal aberrations, and oxidative DNA damage (comet assay and 8-OHdG) among Pb-exposed than the unexposed. However, studies included in the review exhibited high levels of heterogeneity among the studies. Chronic Pb exposure is associated with DNA damage. However, high-quality, multicentred studies are required to strengthen present observations and further understand the Pb's role in inducing DNA damage. CRD42022286810.

Dose-dependent effects of chronic lead toxicity in vivo: Focusing on trace elements and gut microbiota

Dose-dependent effects of chronic Pb exposure-induced injuries, especially on the trace elements and gut microbiota in mice, have not been explored. In the present study, we investigated these aspects using C57BL/6 mouse models that were exposed to Pb via drinking water with Pb concentrations of 0.1, 0.5, and 1.0 g/L for 8 weeks. The results showed that with the increase in chronic Pb exposure dose, the Pb levels in the blood and tissues, Zn levels in the kidney and brain were elevated, and the levels of bone Zn, kidney Fe, brain Mg, Ca, and Fe, renal catalase activity, and glutathione levels, as well as the expression of colonic zonula occludens-1 and occludin, decreased with a strong linear correlation. Moreover, the relative abundance of Marvinbryantia and Ruminococcus 1 increased, while that of Lactobacillus and Roseburia decreased linearly with the Pb exposure dose. PICRUSt analysis revealed that chronic Pb exposure had a greater impact on the metabolism of macronutrients, trace elements, and neurodegenerative injury. These findings suggest that chronic Pb exposure disrupts trace element levels in tissues, especially in the brain, and induces gut dysbiosis in a dose-dependent manner, which is different from the dose-effect of acute Pb toxicity.

Age-related miRNAs dysregulation and abnormal BACE1 expression following Pb exposure in adolescent mice.

Numbers of emerging evidence suggest that lead (Pb) exposure contributes to cognitive decline and might also increase the risk of Alzheimer's disease (AD) dementia in the elderly by increasing the beta-amyloid burden. Here, we aimed to characterize the effects of Pb on the post-transcriptional regulators, microRNAs (miRNAs), which may participate in AD pathogenesis. At first, early chronic Pb exposure on neuronal miRNAs expression with increasing aging was profiled to elucidate the association of three selected miRNAs with β-site APP-cleaving enzyme 1(BACE1), a rate-limiting enzyme for β-amyloid (Aβ) production. Next, we verified changes in BACE1 were observed by regulating miRNAs expression in vitro. While Pb promoted BACE1 levels, BACE1 levels were reduced in SH-SY5Y cells with miR-124-3p mimic, suggesting for the first time that miR-124-3p/BACE1 pathway modulation is critically involved in Pb-induced AD-like amyloidogenic processing. Findings from this study could provide new insight into the molecular mechanisms of Pb-associated neurodegenerative pathogenesis from an epigenetic perspective.

Effects of Sub-chronic Lead Exposure on Essential Element Levels in Mice.

Lead (Pb), a corrosion-resistant heavy non-ferrous metal, is one of the most common environmental neurotoxic metals. The effects of Pb on other essential metal elements are contradictory. Therefore, this in vivo study addressed the effects of sub-chronic Pb exposure on the distribution of other divalent metals, exploring the relationships between Pb levels in blood, teeth, bones, hair, and brain tissues. Thirty-two healthy male C57BL/6 mice received intragastric administration (i.g.) with 0, 12.5, 25, and 50mg/kg Pb acetate, once a day for 8weeks. Levels of Pb and other metal elements [including iron(Fe), zinc (Zn), magnesium (Mg), copper (Cu), and calcium(Ca)] in the whole blood, teeth, the right thighbone, hair, and brain tissues (including cortex, hippocampus, striatum, and hypothalamus) were detected with inductively coupled plasma-mass spectrometry (ICP-MS). Pb levels in all detectedorgans were increased after Pb-exposed for 8weeks. The results of relationship analysis between Pb levels in the tissues and lifetime cumulative Pb exposure (LCPE) showed that Pb levels in the blood, bone, and hair couldindirectly reflect the Pb accumulation in the murine brain. These measures might serve as valuable biomarkers for chronic Pb exposure reflective of the accumulation of Pb in the central nervous system (CNS). Sub-chronic Pb exposure for 8weeks altered Ca, Cu, Fe, and Zn levels, but no effects were noted on Mg levels in any of the analyzed tissues. Pb decreased Ca in teeth, Cu in thighbone and teeth, Zn in whole blood and hair, and Fe in hair. In contrast, Pb increased Ca levels in corpus striatum and hypothalamus, Cu levels in striatum, Zn levels in teeth, and Fe levels in hippocampus, thighbone, and teeth. The Pb-induced changes in metal ratios in various tissues may serve as valuable biomarkers for chronic Pb exposure as they are closely related to the accumulations of Pb in the murine CNS. The results suggest that altered distribution of several essential metal elements may be involved in Pb-induced neurotoxicity. Additional studies should address the interaction between Pb and essential metal elements in the CNS and other organs.

Association between blood lead levels and markers of calcium homeostasis: a systematic review and meta-analysis

Chronic Pb exposure associated systemic illness are partly posited to involve calcium homeostasis. Present systematic review aims to comprehensively evaluate the association between chronic lead exposure and markers of calcium homeostasis. Observational studies documenting the changes in calcium homeostasis markers (i.e. serum calcium, parathyroid hormone, vitamin D & calcitonin) between occupationally Pb exposed group and control group were systematically searched from pubmed-Medline, Scopus, and Embase digital databases since inception to September 24, 2021. The protocol was earlier registered at PROSPERO (ID: CRD42020199503) and executed adhering to PRISMA 2020 guidelines. Mean differences of calcium homeostasis markers between the groups were analysed using random-effects model. Conventional I2 statistics was employed to assess heterogeneity, while the risk for various biases were assessed using Newcastle Ottawa Scale. Sub-group, sensitivity and meta-regression analyses were performed where data permitted. Eleven studies including 837 Pb exposed and 739 controls were part of the present study. Pb exposed group exhibited higher mean blood lead level [i.e. 36.13 (with 95% CI 25.88–46.38) µg/dl] significantly lower serum calcium (i.e. − 0.72 mg/dl with 95% CI − 0.36 to − 1.07) and trend of higher parathyroid levels and lower vitamin D levels than controls. Heterogeneity was high (I2 > 90%) among the studies. Considering the cardinal role of calcium in multiple biological functions, present observations emphasis the need for periodic evaluation of calcium levels and its markers among those with known cumulative Pb exposure.