Low-dose Exposure Research Articles

Lycopene supplementation: effects on oxidative stress, sex hormones, gonads and thyroid tissue in tilapia Oreochromis niloticus during Harness® exposure.

Harness® is a commercial herbicide that contains acetochlor at a concentration of 84% as an active ingredient. Ubiquitous, persistent, and substantial uses of Harness® in agricultural processes have resulted in the pollution of nearby water sources, posing a threat to various aquatic biotas, including fish. The effects of Harness® toxicity on fish health are little known. So, this study aimed to describe the impact of herbicide Harness® on the oxidative stress and reproductive and thyroid performance of male and female tilapia (Oreochromis niloticus) and also investigate the prospective role of the natural antioxidant lycopene supplementation in dismissing the adverse properties of Harness®. Antioxidant enzyme (catalase, superoxide dismutase, and total antioxidant capacity) and hormone measurements (T, E2, T3, and T4) were carried out, and gonadal and thyroid follicle histological sections were examined as a method to investigate the effects of Harness® toxicity on fish. Male and female tilapia were exposed to 10μmol/L and 100μmol/L of Harness® and treated with 10mg lycopene/kg for 15days of exposure. Our results demonstrated that the antioxidant enzyme activity was altered by Harness exposure and serum T for both males and females dropped; also, female E2 levels decreased, but male E2 increased. Exposure to higher dose of Harness® induced elevation in both T3 and T4 levels, although the low exposure dose stimulated T4 levels. Harness® exposure prompted histological variations and degenerative changes in testicular, ovarian, and thyroid follicle tissues. Lycopene supplement administration diminished oxidative stress induced by Harness®, alleviating its endocrine disparaging effects by neutralizing T3, T4, T, and E2 and ameliorating the histological structure of gonadal and thyroid tissues. In conclusion, lycopene supplementation was preformed to normalize the alterations and oxidative damage caused by Harness® in Nile tilapia, suggesting that lycopene-supplemented diet functioned as potent antioxidants and had the ability to alleviate oxidative stress and thyroid and reproductive toxicity caused by herbicide Harness®. Moreover, it is crucial to take appropriate care when consuming herbicides to defend the aquatic environment.

Low-dose radiation induces unstable gene expression in developing human iPSC-derived retinal ganglion organoids

The effects of low-dose radiation on undifferentiated cells carry important implications. However, the effects on developing retinal cells remain unclear. Here, we analyzed the gene expression characteristics of neuronal organoids containing immature human retinal cells under low-dose radiation and predicted their changes. Developing retinal cells generated from human induced pluripotent stem cells (iPSCs) were irradiated with either 30 or 180 mGy on days 4–5 of development for 24 h. Genome-wide gene expression was observed until day 35. A knowledge-based pathway analysis algorithm revealed fluctuations in Rho signaling and many other pathways. After a month, the levels of an essential transcription factor of eye development, the proportion of paired box 6 (PAX6)-positive cells, and the proportion of retinal ganglion cell (RGC)-specific transcription factor POU class 4 homeobox 2 (POU4F2)-positive cells increased with 30 mGy of irradiation. In contrast, they decreased after 180 mGy of irradiation. Activation of the “development of neurons” pathway after 180 mGy indicated the dedifferentiation and development of other neural cells. Fluctuating effects after low-dose radiation exposure suggest that developing retinal cells employ hormesis and dedifferentiation mechanisms in response to stress.

Low-dose antimony exposure promotes prostate cancer proliferation by inhibiting ferroptosis via activation of the Nrf2-SLC7A11-GPX4 pathway

Antimony (Sb) is a typical environmental pollutant. With the development of industrialization, antimony is widely used in daily life and enters the human body through the food chain, water source, air pollution, and other channels. The risk of antimony exposure has emerged as one of the public's major health concerns. Current research on antimony shows that antimony has certain biological toxicity, and antimony exposure may be one of the carcinogenic risk factors for bladder cancer, prostate cancer (PCa), and other cancers. But the molecular mechanism of antimony exposure in PCa is still unclear. Our results showed that serum antimony levels were significantly higher in PCa patients than in benign prostatic hyperplasia (BPH), and high levels of serum antimony were associated with poorer prognosis in PCa. We demonstrate that antimony exposure promotes PCa progression in vivo and in vitro. In addition, our results also showed that low-dose antimony exposure resulted in increased GSH, increased GPX4 expression, and decreased Fe2+. Since GPX4 and Fe2+ are important molecular features in the mechanism of ferroptosis, we further found that low-dose antimony exposure can inhibit RSL3-induced ferroptosis and promote PCa proliferation. Finally, our study demonstrates that low-dose antimony exposure promotes Nrf2 expression, increases the expression level of SLC7A11, and then increases the expression of GPX4, inhibits ferroptosis, and promotes PCa progression. Taken together, our experimental results suggest that low-dose antimony exposure promotes PCa cell proliferation by inhibiting ferroptosis through activation of the Nrf2-SLC7A11-GPX4 pathway. These findings highlight the link between low-dose antimony exposure and the Nrf2-SLC7A11-GPX4 ferroptosis pathway, providing a new potential direction for the prevention and treatment of PCa.

The challenges of defining hormesis in epidemiological studies: The case of radiation hormesis

In the current radiation protection system, preventive measures and occupational exposure limits for controlling occupational exposure to ionizing radiation are based on the linear no-threshold extrapolation model. However, currently an increasing body of evidence indicates that this paradigm predicts very poorly biological responses in the low-dose exposure region. In addition, several in vitro and in vivo studies demonstrated the presence of hormetic dose response curves correlated to ionizing radiation low exposure. In this regard, it is noteworthy that also the findings of different epidemiological studies, conducted in different categories of occupationally exposed workers (e.g., healthcare, nuclear industrial and aircrew workers), observed lower rates of mortality and/or morbidity from cancer and/or other diseases in exposed workers than in unexposed ones or in the general population, then suggesting the possible occurrence of hormesis. Nevertheless, these results should be considered with caution since the identification of hormetic response in epidemiological studies is rather challenging because of a number of major limitations. In this regard, some of the most remarkable shortcomings found in epidemiological studies performed in workers exposed to ionizing radiation are represented by lack or inadequate definition of exposure doses, use of surrogates of exposure, narrow dose ranges, lack of proper control groups and poor evaluation of confounding factors. Therefore, considering the valuable role and contribution that epidemiological studies might provide to the complex risk assessment and management process, there is a clear and urgent need to overcome the aforementioned limits in order to achieve an adequate, useful and more real-life risk assessment that should also include the key concept of hormesis. Thus, in the present conceptual article we also discuss and provide possible approaches to improve the capacity of epidemiological studies to identify/define the hormetic response and consequently improve the complex process of risk assessment of ionizing radiation at low exposure doses.

Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an invivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was generated. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. While at 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor γ expression. Surprisingly, Pik3caH1047R mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.

Vapor‐Phase Infiltrated Organic–Inorganic Positive‐Tone Hybrid Photoresist for Extreme UV Lithography

AbstractContinuing extreme downscaling of semiconductor devices, essential for high performance and energy efficiency of future microelectronics, hinges on extreme ultraviolet lithography (EUVL) and addressing associated challenges. One of such challenges is a need for improved EUV photoresists featuring simultaneously high sensitivity, resolution, and etch selectivity. Here, a new, positive‐tone, organic–inorganic hybrid EUV photoresist is demonstrated that delivers a high‐resolution EUVL and electron‐beam lithography (EBL) patterning capability combined with high sensitivity and etch resistance. The new resist, poly(methyl methacrylate) infiltrated with indium oxide (PMMA‐InOx), is synthesized via vapor‐phase infiltration (VPI), a material hybridization technique derived from atomic layer deposition. The weak binding of the gaseous indium precursor, trimethylindium, to the carbonyl group in PMMA allows the synthesis of hybrids with inorganic content distributed uniformly in the resist, enabling high EUVL and EBL sensitivities (18 mJ cm−2 and 300 µC cm−2, respectively) and high‐resolution positive‐tone EUVL patterning (e.g., 40 nm half‐pitch line‐space and 50 nm diameter contact hole patterns) with high Si etch selectivity (>30–40). The low exposure doses required to pattern the PMMA‐InOx hybrid resist, high etch resistance, and processing strategies, which are developed, can pave the way for using infiltration‐synthesized hybrid thin films as reliable positive‐tone EUV photoresists for future semiconductor patterning.

NMR metabolomics study of chronic low-dose exposure to a cocktail of persistent organic pollutants.

Nowadays, exposure to endocrine-disrupting chemicals (EDCs), including persistent organic pollutants (POPs), is one of the most critical threats to public health. EDCs are chemicals that mimic, block, or interfere with hormones in the body's endocrine system and have been associated with a wide range of health issues. This innovative, untargeted metabolomics study investigates chronic low-dose internal exposure to a cocktail of POPs on multiple tissues that are known to accumulate these lipophilic compounds. Interestingly, the metabolic response differs among selected tissues/organs in mice. In the liver, we observed a dynamic effect according to the exposure time and the doses of POPs. In the brain tissue, the situation is the opposite, leading to the conclusion that the presence of POPs immediately gives a saturated effect that is independent of the dose and the duration of exposure studied. By contrast, for the adipose tissues, nearly no effect is observed. This metabolic profiling leads to a holistic and dynamic overview of the main metabolic pathways impacted in lipophilic tissues by a cocktail of POPs.

Cadmium promotes colorectal cancer metastasis through EGFR/Akt/mTOR signaling cascade and dynamics

Cadmium (Cd) is a hazardous environmental heavy metal with a prolonged biological half-life. Due to the main route of foodborne exposure, the intestinal tract is particularly vulnerable to Cd-induced toxicity. However, the chronic toxicity and underlying mechanisms of Cd in intestinal diseases, including colorectal cancer (CRC), still remain vague. Herein, we aim to investigate the long-term effects of Cd exposure on CRC development and the key signaling event. Our findings indicate that chronic and low-dose exposure to Cd promoted the invasion and metastasis capability of CRC cells in vitro and in mice, with a marginal increase in cell growth. The expression of cell junction-related genes was down-regulated while those molecules that facilitate cell mobility were significantly increased by Cd exposure. Epidermal growth factor receptor (EGFR) signaling was identified to play the dominant role in Cd-promoted CRC metastasis. Interestingly, Cd activated EGFR in a non-canonical manner that exhibited distinct signaling dynamics from the canonical ligand. In contrast to EGF, which induced transient EGFR signaling and ERK activation, Cd promoted sustained EGFR signaling to trigger Akt/mTOR cascade. The unique signaling dynamics of EGFR induced by Cd provoked responses that preferably enhanced the metastatic capacity rather than the growth. Furthermore, blockade of EGFR abrogated the promoting effects of Cd on the liver metastasis of CRC cells. In conclusion, this study provides a better understanding of the long-term influences of environmental Cd on CRC metastasis and reveals the unique EGFR signaling dynamics induced by Cd exposure.

Features of the response to subchronic low-dose exposure to copper oxide nanoparticles in rats

Copper is an essential trace element for human health and, at the same time, a major industrial metal widely used both in its elemental form and in compounds. We conducted a dose-dependent assessment of the response of outbred albino male rats to subchronic low-dose exposure to copper oxide nanoparticles administered intraperitoneally at cumulative doses of 18 and 36 mg/kg during 6 weeks to exposure groups 1 and 2, respectively. We observed disorders at different levels of organization of the body in the exposed animals, from molecular to organismal. The observed decrease in the activity of succinate dehydrogenase in nucleated blood cells gave evidence of impaired bioenergetics processes. In view of the results of the metabolomics analysis, we assume mitochondrial damage and contribution of apoptotic processes to the pathology induced by copper poisoning. We also assume neurodegenerative effects based on the assessed morphological parameters of the nervous system, results of behavioral tests, and a decreased level of expression of genes encoding NMDA receptor subunits in the hippocampus. The hepatotoxic effect noted by a number of metabolomics-based, biochemical, and cytological indicators was manifested by the impaired protein-synthesizing function of the liver and enhanced degenerative processes in its cells. We also observed a nephrotoxic effect of nanosized copper oxide with a predominant lesion of proximal kidney tubules. At the same time, both doses tested demonstrated such positive health effects as a statistically significant decrease in the activity of alkaline phosphatase and the nucleated blood cell DNA fragmentation factor. Judging by the changes observed, the cumulative dose of copper oxide nanoparticles of 18 mg/kg body weight administered intraperitoneally approximates the threshold one for rats. The established markers of health impairments may serve as a starting point in the development of techniques of early diagnosis of copper poisoning.

Impacts of Indoor Dust Exposure on Human Colonic Cell Viability, Cytotoxicity and Apoptosis.

Environmental exposure to indoor dust is known to be associated with myriad health conditions, especially among children. Established routes of exposure include inhalation and non-dietary ingestion, which result in the direct exposure of gastrointestinal epithelia to indoor dust. Despite this, little prior research is available on the impacts of indoor dust on the health of human gastrointestinal tissue. Cultured human colonic (CCD841) cells were exposed for 24 h to standard trace metal dust (TMD) and organic contaminant dust (OD) samples at the following concentrations: 0, 10, 25, 50, 75, 100, 250, and 500 µg/mL. Cell viability was assessed using an MTT assay and protease analysis (glycyl-phenylalanyl-aminofluorocoumarin (GF-AFC)); cytotoxicity was assessed with a lactate dehydrogenase release assay, and apoptosis was assessed using a Caspase-Glo 3/7 activation assay. TMD and OD decreased cellular metabolic and protease activity and increased apoptosis and biomarkers of cell membrane damage (LDH) in CCD841 human colonic epithelial cells. Patterns appeared to be, in general, dose-dependent, with the highest TMD and OD exposures associated with the largest increases in apoptosis and LDH, as well as with the largest decrements in metabolic and protease activities. TMD and OD exposure were associated with markers of reduced viability and increased cytotoxicity and apoptosis in human colonic cells. These findings add important information to the understanding of the physiologic effects of indoor dust exposure on human health. The doses used in our study represent a range of potential exposure levels, and the effects observed at the higher doses may not necessarily occur under typical exposure conditions. The effects of long-term, low-dose exposure to indoor dust are still not fully understood and warrant further investigation. Future research should explore these physiological mechanisms to further our understanding and inform public health interventions.

Effects of Polystyrene Microparticles on Growth and Physiological Metabolism of Microalgae Scendesmus obliquus

Plastic products are widely used due to their lightness, durability, low cost, and malleability, and their threat to the environment is becoming increasingly apparent. However, the detailed mechanism of such an effect is unclear. Due to improper treatment, microplastic contamination is very much studied in the areas around sewage outfalls or some plastic manufacturers, and its content is high. To investigate the ecological impact of microplastics in this particular area, we evaluated the toxic effect of polystyrene microplastics (PS-MPs) on the microalgae Scenedesmus obliquus (S. obliquus). In particular, the cell growth, photosynthesis, antioxidant enzyme activity, membrane permeability, and morphology of the microalgae in the presence of different PS-MP concentrations were monitored. These new data revealed an increase in microalgae cell growth as an early response to low-dose PS-MP exposure with a maximum inhabitation rate of −3.33%. In contrast, a higher concentration of PS-MP solution leads to a significant inhibition within the test concentration, with a maximum inhabitation rate of 43.62%. Meanwhile, a decreased photosynthesis activity of S. obliquus was observed during the exposure. Moreover, PS-MPs induced oxidative damage to the algae cells, exhibiting decreased antioxidant activities and enhanced lipid peroxidation reactions, as evidenced by the reduction in the superoxide dismutase (SOD) level and increased malondialdehyde (MDA) content, as well as damaged cell membrane and soluble protein. Collectively, our study systematically investigates the toxicity of microplastics on microalgae, providing a deep insight into the possible influences of plastic pollution on the whole food web in the aquatic ecosystem.

Low-dose bisphenols exposure sex-specifically induces neurodevelopmental toxicity in juvenile rats and the antagonism of EGCG

Bisphenols (BPs) can negatively affect neurobehaviors in rats, whereas the mechanism remains unclear. Here, the mechanism of BPs-induced neurodevelopmental toxicity and its effective detoxification measures were investigated in vitro and in vivo. In in vitro experiments, primary hippocampal neurons from neonatal rats of different genders were treated with bisphenol A (BPA), bisphenol S (BPS) and bisphenol B (BPB) at 1 nM-100 μM, epigallocatechin gallate (EGCG) and G15, an antagonist of G protein-coupled estrogen receptor (GPER) for 7 d. Results indicated that BPs affected neuronal morphogenesis, impaired GABA synthesis and Glu/GABA homeostasis. Neuronal morphogenetic damage induced by low-doses BPA may be mediated by GPER. Neurotoxicity of BPS is weaker than BPA and BPB. In in vivo studies, exposure to BPA (0.5 μg/kg·bw/day) on PND 10–40 caused oxidative stress and inflammation in rat hippocampus, disrupted neuronal morphogenesis and neurotransmitter homeostasis, ultimately impaired spatial memory of rats. Males are more sensitive to BPA exposure than females. Both in vivo and in vitro studies indicated that EGCG, a phytoestrogen, can alleviate BPA-induced neurotoxicity. Taken together, low-doses BPA exposure sex-specifically disrupted neurodevelopment and further impaired learning and memory ability in rats, which may be mediated by GPER. Promisingly, EGCG effectively mitigated the BPA-induced neurodevelopmental toxicity.

Accumulation and glucocorticoid signaling suppression by four emerging perfluoroethercarboxylic acids based on animal exposure and cell testing

Various perfluoroethercarboxylic acids (PFECA) have emerged as next-generation replacements of legacy per- and polyfluoroalkyl substances (PFAS). However, there is a paucity of information regarding their bioaccumulation ability and hazard characterization. Here, we explored the accumulation and hepatotoxicity of four PFECA compounds (HFPO-DA, HFPO-TA, PFO4DA, and PFO5DoDA) in comparison to perfluorooctanoic acid (PFOA) after chronic low-dose exposure in mice. Except for HFPO-DA, the levels of all tested PFAS in the liver exceeded that in serum. High molecular weight PFECA compounds (PFO5DoDA and HFPO-TA) showed stronger accumulation capacity and longer half-lives (t1/2) than low molecular weight PFECA compounds (HFPO-DA and PFO4DA) and even legacy PFOA. Although hepatomegaly is a common apical end point of PFAS exposure, the differentially expressed gene (DEG) profiles in the liver suggested significant differences between PFOA and the four PFECA compounds. Gene enrichment analysis supported a considerable inhibitory effect of PFECA, but not PFOA, on the glucocorticoid receptor (GR) signaling pathway. Both HFPO-TA and PFO5DoDA demonstrated a more pronounced ability to perturb RNA expression profiles in vivo and to suppress GR signaling in vitro compared to HFPO-DA and PFO4DA. Calculated reference doses (RfDs) emphasized the potential hazard of PFECA to human health. Overall, our findings indicate that PFECA alternatives do not ease the concerns raised from legacy PFAS pollution.

A single priming event prevents oral tolerance to peanut.

Indoor dust (ID) is a source of peanut proteins and immunostimulatory adjuvants (e.g. LPS) that can promote airway sensitization to peanut. We aimed to determine whether a single airway exposure to peanut plus adjuvant is sufficient to prevent oral tolerance. To determine the effect of a single priming event, C57BL/6J mice were exposed once to peanut plus adjuvant through the airway, followed by either airway or low-dose oral exposure to peanut, and assessed for peanut allergy. Oral tolerance was investigated by feeding high-dose peanut followed by airway sensitization. To determine whether a single priming could prevent oral tolerance, the high-dose peanut regimen was applied after a single airway exposure to peanut plus adjuvant. Peanut-specific IgE and IgG1 were quantified, and mice were challenged to peanut to assess allergy. Peanut-specific CD4+ memory T cells (CD4+ TCRβ+ CD44hi CD154+ ) were quantified in mediastinal lymph nodes following airway priming. Mice co-exposed to peanut with LPS or ID through the airway were primed to develop peanut allergy after subsequent low-dose oral or airway exposures to peanut. Oral tolerance was induced in mice fed high-dose peanut prior to airway sensitization. In contrast, mice fed high-dose peanut following a single airway exposure to peanut plus adjuvant led to allergy. Peanut-specific CD4+ memory T cells were detected as early as 7 days after the single airway priming with peanut plus adjuvant, however, delaying peanut feeding even 1 day following priming led to allergy, whereas peanut feeding the same day as priming led to tolerance. A single airway exposure to peanut plus adjuvant is sufficient to prime the immune system to develop allergy following subsequent high-dose oral exposure. These results highlight the importance of introducing peanut as early as possible to prevent sensitization through a non-oral priming event.

Connection between health risk and heavy metals in agricultural soils of China: a study based on current field investigations.

Heavy metal pollution in agricultural soil is a threat to people's health and sustainable development. However, there is currently no nationwide health risk assessment in China. In this study, we performed a preliminary assessment of heavy metals in agricultural soils of the Chinese mainland, and found obvious carcinogenic risks (total lifetime carcinogenic risk (TLCR) > 1 × 10-5). A similar spatial distribution pattern was found in soil heavy metal and the mortality of esophagus and stomach cancers. Combining the potential carcinogenic risk assessed by LCR for individual heavy metal with Pearson correlation, Geographical Detector (q statistic > 0.75 for TLCR, p < 0.05), and redundancy analysis (RDA), it was found that long-term exposure and intake route of heavy metals exceeding the maximum safety threshold (Health Canada standard) may induce digestive system (esophagus, stomach, liver, and colorectum) cancers in rural populations. Through Partial Least Squares Path Model (PLS-PM), it was also revealed that the LCR of heavy metals was closely related to the soil environmental background (path coefficients = 0.82), which in turn was affected by factors such as economic development and pollution discharge. The current research results highlight the potential carcinogenic risk to the digestive system associated with low-dose and long-term exposure to heavy metals in agricultural soils, and policymakers should propose countermeasures and solutions according to the local conditions.

Hippocampal LIMK1-mediated Structural Synaptic Plasticity in Neurobehavioral Deficits Induced by a Low-dose Heavy Metal Mixture.

Humans are commonly exposed to the representative neurotoxic heavy metals lead (Pb), cadmium (Cd), and mercury (Hg). These three substances can be detected simultaneously in the blood of the general population. We have previously shown that a low-dose mixture of these heavy metals induces rat learning and memory impairment at human exposure levels, but the pathogenic mechanism is still unclear. LIM kinase 1 (LIMK1) plays a critical role in orchestrating synaptic plasticity during brain function and dysfunction. Hence, we investigated the role of LIMK1 activity in low-dose heavy metal mixture-induced neurobehavioral deficits and structural synaptic plasticity disorders. Our results showed that heavy metal mixture exposure altered rat fear responses and spatial learning at general population exposure levels and that these alterations were accompanied by downregulation of LIMK1 phosphorylation and structural synaptic plasticity dysfunction in rat hippocampal tissues and cultured hippocampal neurons. In addition, upregulation of LIMK1 phosphorylation attenuated heavy metal mixture-induced structural synaptic plasticity, dendritic actin dynamics, and cofilin phosphorylation damage. The potent LIMK1 inhibitor BMS-5 yielded similar results induced by heavy metal mixture exposure and aggravated these impairments. Our findings demonstrate that LIMK1 plays a crucial role in neurobehavioral deficits induced by low-dose heavy metal mixture exposure by suppressing structural synaptic plasticity.

Cardiac Toxicity Induced by Long-Term Environmental Levels of MC-LR Exposure in Mice.

Cyanobacterial blooms are considered a serious global environmental problem. Recent studies provided evidence for a positive association between exposure to microcystin-LR (MC-LR) and cardiotoxicity, posing a threat to human cardiovascular health. However, there are few studies on the cardiotoxic effects and mechanisms of long-term low-dose MC-LR exposure. Therefore, this study explored the long-term toxic effects and toxic mechanisms of MC-LR on the heart and provided evidence for the induction of cardiovascular disease by MC-LR. C57BL/6 mice were exposed to 0, 1, 30, 60, 90, and 120 μg/L MC-LR via drinking water for 9 months and subsequently necropsied to examine the hearts for microstructural changes using H&E and Masson staining. The results demonstrated fibrotic changes, and qPCR and Western blots showed a significant up-regulation of the markers of myocardial fibrosis, including TGF-β1, α-SMA, COL1, and MMP9. Through the screening of signaling pathways, it was found the expression of PI3K/AKT/mTOR signaling pathway proteins was up-regulated. These data first suggested MC-LR may induce myocardial fibrosis by activating the PI3K/AKT/mTOR signaling pathway. This study explored the toxicity of microcystins to the heart and preliminarily explored the toxic mechanisms of long-term toxicity for the first time, providing a theoretical reference for preventing cardiovascular diseases caused by MC-LR.

Late Effects of Chronic Low Dose Rate Total Body Irradiation on the Heart Proteome of ApoE-/- Mice Resemble Premature Cardiac Ageing.

Recent epidemiologic studies support an association between chronic low-dose radiation exposure and the development of cardiovascular disease (CVD). The molecular mechanisms underlying the adverse effect of chronic low dose exposure are not fully understood. To address this issue, we have investigated changes in the heart proteome of ApoE deficient (ApoE-/-) C57Bl/6 female mice chronically irradiated for 300 days at a very low dose rate (1 mGy/day) or at a low dose rate (20 mGy/day), resulting in cumulative whole-body doses of 0.3 Gy or 6.0 Gy, respectively. The heart proteomes were compared to those of age-matched sham-irradiated ApoE-/- mice using label-free quantitative proteomics. Radiation-induced proteome changes were further validated using immunoblotting, enzyme activity assays, immunohistochemistry or targeted transcriptomics. The analyses showed persistent alterations in the cardiac proteome at both dose rates; however, the effect was more pronounced following higher dose rates. The altered proteins were involved in cardiac energy metabolism, ECM remodelling, oxidative stress, and ageing signalling pathways. The changes in PPARα, SIRT, AMPK, and mTOR signalling pathways were found at both dose rates and in a dose-dependent manner, whereas more changes in glycolysis and ECM remodelling were detected at the lower dose rate. These data provide strong evidence for the possible risk of cardiac injury following chronic low dose irradiation and show that several affected pathways following chronic irradiation overlap with those of ageing-associated heart pathology.

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.

Assessment of thyroid nodule malignancy risk in medical radiation workers using ACR TI-RADS

BackgroundLow-dose radiation exposure brings medical radiation professionals at risk for thyroid parenchymal disease and nodules. ObjectiveTo classify thyroid nodules in medical radiation workers according to their risk, and to look into parenchymal disease and thyroid dysfunction. Design, setting and participantsRetrospective observational study in a tertiary health facility with 148 healthcare workers working in radiation-containing areas. Main outcome and measuresParticipants were divided into groups based on their sociodemographic characteristics, the department they worked in, and the number of years they had been in the profession. The levels of TSH, parenchymal heterogeneity, and thyroid nodule presence were compared between the groups. American College of Radiology (ACR) Thyroid Imaging – Reporting and Data System (TI-RADS) classification was used to evaluate thyroid nodules. ResultsThe presence of nodules was significantly more prevalent in patients over the age of 33 (p = 0.02). The majority of individuals (98%) had nodules that below the American College of Radiology (ACR) Thyroid Imaging – Reporting and Data System (TI-RADS) category 4. Age and professional experience both elevated TSH results (p = 0.015, p = 0.033). With age, parenchymal heterogeneity became more prominent (p = 0.04). For the parameters, there were no appreciable differences between the occupation and department. The results applied to both genders equally. ConclusionWith increasing long-term low-dose exposure, medical radiation workers are at risk for nodules and parenchymal disease. However, the majority of the nodules in our study were sonographically in the low risk group, therefore routine follow-up is advised.