Qiao Niu

Palladium nanoparticles induce disturbances in cell cycle entry and progression of peripheral blood mononuclear cells: paramount role of ions.

There is concern about the possible toxicity of palladium nanoparticles (Pd-NP), as they are released in the environment through many applications. We previously studied the toxicity of Pd-NP at high concentrations; here we address the possible toxicity of Pd-NP at low, subtoxic doses. In particular, we have exposed normal human PBMC entering into the first in vitro mitotic division to Pd-NP and to Pd(IV) ions to evaluate ROS generation and cell cycle progression. We have measured a statistically significant increase of intracellular ROS in Pd(IV) exposed cells, but not in Pd-NP exposed cells. TEM revealed accumulation of lipid droplets and autophagic and mitophagic vacuoles, which appeared more conspicuous in cells exposed to Pd(IV) ions than to Pd-NP. Pd-NP were visible in the cytoplasm of Pd-NP exposed cells. Pd-NP addition was associated with a significant increase of cells within the G0/G1-phase and a significant reduction in GS- and G2/M-phases. Cells exposed to Pd(IV) ions showed a significant amplification of these cell cycle alterations. These results suggest that ions, per se or released by NPs, are the true inducers of Pd toxicity. It will be essential to verify whether the observed disturbance represents a temporary response or might result in permanent alterations.

Engineered metal based nanoparticles and innate immunity

Almost all people in developed countries are exposed to metal nanoparticles (MeNPs) that are used in a large number of applications including medical (for diagnostic and therapeutic purposes). Once inside the body, absorbed by inhalation, contact, ingestion and injection, MeNPs can translocate to tissues and, as any foreign substance, are likely to encounter the innate immunity system that represent a non-specific first line of defense against potential threats to the host. In this review, we will discuss the possible effects of MeNPs on various components of the innate immunity (both specific cells and barriers). Most important is that there are no reports of immune diseases induced by MeNPs exposure: we are operating in a safe area. However, in vitro assays show that MeNPs have some effects on innate immunity, the main being toxicity (both cyto- and genotoxicity) and interference with the activity of various cells through modification of membrane receptors, gene expression and cytokine production. Such effects can have both negative and positive relevant impacts on humans. On the one hand, people exposed to high levels of MeNPs, as workers of industries producing or applying MeNPs, should be monitored for possible health effects. On the other hand, understanding the modality of the effects on immune responses is essential to develop medical applications for MeNPs. Indeed, those MeNPs that are able to stimulate immune cells could be used to develop of new vaccines, promote immunity against tumors and suppress autoimmunity.

Benzo[a]pyrene-induced neurobehavioral function and neurotransmitter alterations in coke oven workers

Objective To study alterations in neurobehavioral function and neurotransmitter levels in coke oven workers occupationally exposed to benzo[a]pyrene (B[a]P) and explore possible biomarkers of B[a]P neurotoxicity. Methods 176 coke oven workers occupationally exposed to B[a]P and 48 warehouse workers (controls) were investigated by questionnaire. Emotional and cognitive function was investigated using the WHO/NCTB. B[a]P concentrations in the working environment, concentrations of monoamine and amino acid neurotransmitters, and levels of urinary 1-hydroxypyrene (1-OH-Py) were assayed by HPLC. Spectrophotometry was used to determine choline neurotransmitter concentrations. Results Airborne B[a]P concentrations were higher in the coke oven plant than in the controls workplace, and 1-OH-Py levels were significantly increased in coke workers compared to controls (p=0.000). Digital span and order digital span scores indicated that learning and memory were significantly decreased in coke oven workers (p=0.006). Concentrations of norepinephrine (NE), dopamine, 5-hydroxytryptamine and homovanillic acid were lower, while levels of 5-hydroxyindoleacetic acid were higher in the exposed group compared to controls; the difference in NE was significant (p=0.000). Aspartic acid and gamma-aminobutyric acid levels were significantly decreased in coke oven workers compared to controls (p=0.004 and p=0.004). Acetylcholine (Ach) concentration was four- to fivefold greater in coke oven workers than in controls, while acetylcholine esterase (AchE) activity was significantly decreased (p=0.000 and p=0.012). Statistical analysis showed that digital span and order digital span scores were negatively correlated to Ach and positively correlated to AchE. Conclusion Occupational B[a]P exposure may reduce coke oven workers neurobehavioral function and monoamine, amino acid and choline neurotransmitter levels. Moreover, Ach and AchE correlated with neurobehavioral function; AchE has poor specificity, but Ach is a potential biomarker of B[a]P neurotoxicity in coke oven workers.

Effects of Benzo[a]pyrene on Autonomic Nervous System of Coke Oven Workers

Effects of Benzo[a]pyrene on Autonomic Nervous System of Coke Oven Workers: Hong‐Mei Zhang, et al. Department of Occupational Health, School of Public Health, Shanxi Medical University, China—Objectives are to investigate the effects of benzo[a]pyrene (B[a]P) on the autonomic nervous system of coke oven workers. One hundred eightyfour coke oven workers were divided into 3 groups according to their working sites (coke oven bottom group, coke oven side group and coke oven top group), and 93 referents were recruited. B[a]P monitored by air sampling pumps as well as urinary 1‐hydroxypyrene (1‐OH‐Py) was determined by high performance liquid chromatograph with a fluorescence detector (HPLCFD). The autonomic nervous system (ANS) function was determined by 4 tests: Valsalva Manoeuvre heart rate variation (HR‐V), variation of heart rate when breathing deeply (HR‐DB), variation of heart rate when instantly standing up (HR‐IS, including RR30:15 and RRmax:min) and variation of blood pressure when instantly standing up (BP‐IS). The B[a]P mean concentrations in coke oven bottom, coke oven side and coke oven top were 19, 185 and 1,623 ng/m3, respectively. The levels of urinary 1‐OH‐Py were markedly higher in the 3 exposed groups than that in the referent group (p<0.01). No significant difference was found in each group between smokers and nonsmokers (p>0.05). Compared with referents, HR‐V decreased significantly in coke oven workers (p<0.01), representing modulation of parasympathetic nervous function. However, no statistical differences were found in HR‐DB, RR30:15, RRmax:min and BP‐IS between the exposed groups and the control group (p>0.05). HR‐V decreased with the increment of 1‐OH‐Py (p<0.05), and results of multiple linear stepwise regression demonstrated that external exposure level and duration of education entered the HR‐V model; age was a significant factor of HR‐DB and RRmax:min, but no variable was involved in RR30:15 and BP‐IS regression. Benzo[a]pyrene affects the autonomic nervous function of coke oven workers mainly by down‐regulating the parasympathetic nervous function.

Effects of aluminium on β-amyloid (1-42) and secretases (APP-cleaving enzymes) in rat brain.

Chronic administration of aluminium has been proposed as an environmental factor that may affect some pathological changes related to neurotoxicity and Alzheimer’s disease (AD). The abnormal generation and deposition of β-amyloid (Aβ) in senile plaques are hallmark features in the brains of AD patients. Furthermore, Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. In the present study, we investigated the modulation of Aβ deposition and neurotoxicity in aluminium-maltolate-treated (0, 15, 30, 45xa0mmol/kg body weight via intraperitoneal injection) in experimental rats. We measured Aβ1–40 and Aβ1–42 in the cortex and hippocampus in rat brains using ELISA. Subtypes of α-secretase, β-secretase, and γ-secretase, including ADAM9, ADAM10, ADAM17 (TACE), BACE1, presenilin 1 (PS1) and nicastrin (NCT), were determined using western blotting analyses. These results indicated that aluminium-maltolate induced an AD-like behavioural deficit in rats at 30 and 45xa0mmol/kg body weight. Moreover, the Aβ1–42 content increased significantly, both in the cortex and hippocampus, although no changes were observed in Aβ1–40. Furthermore, ADAM9, ADAM10, and ADAM17 decreased significantly; in contrast, BACE1, PS1, and NCT showed significant increase. Taken together, these results suggest that the changes in secretases may correlate to the abnormal deposition of Aβ by aluminium in rat brains.

Lactation exposure to BDE-153 damages learning and memory, disrupts spontaneous behavior and induces hippocampus neuron death in adult rats

OBJECTIVEnTo study the effects of 2,2,4,4,5,5-hexa-brominated diphenyl ether (BDE-153) exposure during lactation on the learning and memory abilities, spontaneous behavior and brain cells of adult rats and to elicit basic information on PBDEs developmental neurotoxicity.nnnMETHODSnNewborn male rat pups were randomly categorized into the following groups (15 pups per group), according to their weights and litters: a control group, and 1mg/kg, 5mg/kg and 10mg/kg BDE-153 groups. At postnatal day 10 (PND10), the pups in the BDE-153 groups were intraperitoneally injected once with BDE-153 plant oil solutions at 0.1ml/10g body weight, and the controls were injected with plant oil. Throughout the entire experiment, physiological measures were recorded, such as food and water consumption, body weight and clinical symptoms. At 1 month and 2 months after treatment, the learning and memory abilities of the rats were tested by the Morris water maze test, the step-down test, and the step-through test; spontaneous behavior was tested by the open-field test. After all tests were accomplished, rats were weighed and sacrificed, and the brain tissue was immediately isolated and divided into two parts. Sections were fabricated from one part, and changes in the morphology and ultrastructure in CA3 region of hippocampus were observed under an optical microscope and transmission electron microscope, along with the detection of apoptotic cells with the terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method. The tissue of the second part was digested into single-cell suspension liquid, and the cell apoptosis was assayed with flow cytometry and the lactate dehydrogenase (LDH) leakage was detected with spectrophotometry.nnnRESULTSnThere was no obvious change in food and water consumption, body weight and the ratio of brain to body weight, or any overt clinical symptoms in the BDE-153-treated rats. Compared to the control group, rats latency time in the test session (LT2) in the step-down test was significantly increased in the 10mg/kg BDE-153 group at 2 months after treatment (P<0.05), and the BDE-153-treated rats swimming times and distances in the target quadrant were significantly decreased at 1 month and 2 months after treatment (P<0.05 or P<0.01). These parameters were also significantly increased in the opposite quadrant at 1 month after treatment (P<0.05 or P<0.01). The spontaneous behavior was significantly reduced in the treated groups compared to the controls (P<0.05 or P<0.01). The severity of neurobehavioral dysfunction was dependent on the exposure dose of BDE-153, and worsened with age. Under an optical microscope, the treated rats neurons in the CA3 region of the hippocampus were observed to be reduced and disarranged, and the cell junctions were loosened and the intercellular spaces were enlarged. Under a transmission electron microscope, the cell nucleus was observed to shrink; the chromatin was condensed and gathered near the nuclear membrane, the Nissl bodies and other organelles in the perikaryon were reduced, and the vacuole was observed to degenerate and even disappear. Moreover, compared to the controls, the cell apoptosis rates were significantly increased in the 5 and 10mg/kg BDE-153 groups (P<0.05), and the LDH activity was significantly increased in the 10mg/kg BDE-153 groups (P<0.01).nnnCONCLUSIONnLactation exposure to BDE-153 damaged adult rats learning and memory abilities, disrupted their spontaneous behavior (hypoactivity) and induced hippocampus neuron apoptosis.

Effects of Exposure to Aluminum on Long-term Potentiation and AMPA Receptor Subunits in Rats in vivo

OBJECTIVEnTo explore the effects of exposure to aluminum (Al) on long-term potentiation (LTP) and AMPA receptor subunits in rats in vivo.nnnMETHODSnDifferent dosages of aluminum-maltolate complex [Al(mal)3] were given to rats via acute intracerebroventricular (i.c.v.) injection and subchronic intraperitoneal (i.p.) injection. Following Al exposure, the hippocampal LTP were recorded by field potentiation technique in vivo and the expression of AMPAR subunit proteins (GluR1 and GluR2) in both total and membrane-enriched extracts from the CA1 area of rat hippocampus were detected by Western blot assay.nnnRESULTSnAcute Al treatment produced dose-dependent suppression of LTP in the rat hippocampus and dose-dependent decreases of GluR1 and GluR2 in membrane extracts; however, no similar changes were found in the total cell extracts, which suggests decreased trafficking of AMPA receptor subunits from intracellular pools to synaptic sites in the hippocampus. The dose-dependent suppressive effects on LTP and the expression of AMPA receptor subunits both in the membrane and in total extracts were found after subchronic Al treatment, indicating a decrease in AMPA receptor subunit trafficking from intracellular pools to synaptic sites and an additional reduction in the expression of the subunits.nnnCONCLUSIONnAl(mal)3 obviously and dose-dependently suppressed LTP in the rat hippocampal CA1 region in vivo, and this suppression may be related to both trafficking and decreases in the expression of AMPA receptor subunit proteins. However, the mechanisms underlying these observations need further investigation.

Cognitive Disorders and Tau-Protein Expression Among Retired Aluminum Smelting Workers

Objectives: To analyze cognitive functions and tau-protein expression in peripheral blood lymphocytes of retired aluminum (Al)-exposed workers. Methods: A total of 66 retired Al potroom workers and 70 unexposed controls were investigated. The cognitive functions were assessed with the Mini-Mental State Examination. The tau-protein expression in peripheral blood lymphocyte was analyzed with Western blot. Results: The cognitive functions of the exposed group were significantly decreased. Twelve mild cognitive impairment cases in the exposed group and four mild cognitive impairment cases in the control group were diagnosed. Significantly higher p-tau181 and p-tau231 levels were detected in the Al-exposed workers than in the control group. Conclusions: The study suggests that long-term exposure to Al may cause cognitive disorders and that p-tau181 and p-tau231 might be useful indicators for monitoring cognitive decline in Al-exposed workers.

Caspase-3 short hairpin RNAs: a potential therapeutic agent in neurodegeneration of aluminum-exposed animal model.

There is abundant evidence supporting the role of caspases in the development of neurodegenerative disease, including Alzheimers disease (AD). Therefore, regulating the activity of caspases has been considered as a therapeutic target. However, all the efforts on AD therapy using pan-caspase inhibitors have failed because of uncontrolled adverse effects. Alternatively, the specific knockdown of caspase-3 gene through RNA interference (RNAi) could serve as a future potential therapeutic strategy. The aim of the present study is to down-regulate the expression of caspase-3 gene using lentiviral vector-mediated caspase-3 short hairpin RNA (LV-Caspase-3 shRNA). The effect of LV-Caspase-3 shRNA on apoptosis induced by aluminum (Al) was investigated in primary cultured cortical neurons and validated in C57BL/6J mice. The results indicated an increase in apoptosis and caspase-3 expression in primary cultured neurons and the cortex ofmice exposed to Al, which could be down-regulated by LV-Caspase-3 shRNA. Furthermore, LV-Caspase-3 shRNA reduced neural cell death and improved learning and memory in C57BL/6J mice treated with Al. Our results suggest that LV-caspase-3 shRNA is a potential therapeutic agent to prevent neurodegeneration and cognitive dysfunction in aluminum- exposed animal models. The findings provide a rational gene therapy strategy for AD.

The Relationship Between Cognitive Impairment and Global DNA Methylation Decrease Among Aluminum Potroom Workers.

Objective: To investigate the relationship between cognitive impairment and global DNA methylation in aluminum (Al) potroom workers. Methods: A total of 366 Al-exposed workers were investigated, and their cognitive functions were assessed with the Mini-Mental State Examination (MMSE). Aluminum in serum was quantified using graphite furnace atomic absorption spectrometry. Global DNA methylation was analyzed in whole blood using an enzyme-linked immunosorbent assay–like reaction. Results: Mini-Mental State Examination scores and global DNA methylation decreased with the increase of serum Al concentration. Forty-three mild cognitive impairment (MCI) people were diagnosed. Global DNA methylation of the MCI was lower than the non-MCI. Multiple logistic analysis showed that the Al-exposed workers had lower global DNA methylation and higher serum Al concentration and were at the higher risk of MCI. Conclusions: Long-term exposure to Al may cause MCI. Mild cognitive impairment was significantly associated with global DNA methylation in blood.