349 research outputs found
Persistent activation of DNA damage signaling in response to complex mixtures of PAHs in air particulate matter
Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are present in air particulate
matter (PM) and have been associated with many adverse human health effects including
cancer and respiratory disease. However, due to their complexity, the risk of exposure to
mixtures is difficult to estimate. In the present study the effects of binary mixtures of
benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) and complex mixtures of PAHs in urban
air PM extracts on DNA damage signaling was investigated. Applying a statistical model to
the data we observed a more than additive response for binary mixtures of BP and DBP on
activation of DNA damage signaling. Persistent activation of checkpoint kinase 1 (Chk1) was
observed at significantly lower concentrations of air PM extracts than BP alone. Activation of
DNA damage signaling was also more persistent in air PM fractions containing PAHs with
more than four aromatic rings suggesting larger PAHs contribute a greater risk to human
health. Altogether our data suggests that human health risk assessment based on additivity
such as toxicity equivalency factor scales may significantly underestimate the risk of
exposure to complex mixtures of PAHs. The data confirms our previous findings with PAHcontaminated
soil (Niziolek-Kierecka et al. 2012) and suggests a possible role for Chk1
Ser317 phosphorylation as a biological marker for future analyses of complex mixtures of
PAHsFormasCancer- och AllergifondenStockholm UniversityEU/FP7 Marie Curie IRG fellowshipAccepte
Benzo[a]pyrene-specific online high-performance liquid chromatography fractionation of air particulate extracts : a tool for evaluating biological interactions.
Benzo[a]pyrene (B[a]P) is a known human carcinogen and is commonly used as a
surrogate for assessing the carcinogenic risk posed by complex mixtures of
polycyclic aromatic hydrocarbons (PAHs) present in air particulate matter (PM).
However, studies have shown that using B[a]P as a surrogate may underestimate the
carcinogenic potential of PAH mixtures, as the risk assessment approach does not
consider interaction effects. Thus, toxicological studies using B[a]P to assess
its carcinogenic potential in environmentally derived complex mixtures, as
opposed to single compound experiments, could improve risk assessment. The
intention of the present study was to develop an online HPLC fractionation system
for the selective removal of B[a]P from air PM extracts. Two serial pyrenylethyl
(PYE) columns enabled selective separation of B[a]P from its isomers and other
PAHs as well as a short fractionation cycle of 30min. One run consisted of three
collection steps: the first fraction contained PAHs eluting earlier than B[a]P,
the second contained B[a]P and the last contained later-eluting PAHs. The
selectivity and recovery of the system was investigated using extracts of
Stockholm air PM samples. The overall recovery for all PAHs was approximately
80%, and the system proved to be selective, as it removed 94% of B[a]P and less
than 3% of benzo[b]fluoranthene from the complex PAH mixture. Exposing human
cells to blanks generated by the fractionation system did not induce cytotoxicity
or DNA damage signalling. In conclusion, the online HPLC system was selective for
B[a]P fractionation whilst minimising run-to-run variation and allowing repeated
fractionations for larger samples due to its relatively short run time.FormasAccepte
Nanomolar levels of PAHs in extracts from urban air induce MAPK signaling in HepG2 cells.
Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants that
occur naturally in complex mixtures. Many of the adverse health effects of PAHs
including cancer are linked to the activation of intracellular stress response
signaling. This study has investigated intracellular MAPK signaling in response
to PAHs in extracts from urban air collected in Stockholm, Sweden and Limeira,
Brazil, in comparison to BP in HepG2 cells. Nanomolar concentrations of PAHs in
the extracts induced activation of MEK4 signaling with down-stream increased gene
expression of several important stress response mediators. Involvement of the
MEK4/JNK pathway was confirmed using siRNA and an inhibitor of JNK signaling
resulting in significantly reduced MAPK signaling transactivated by the AP-1
transcription factors ATF2 and c-Jun. ATF2 was also identified as a sensitive
stress responsive protein with activation observed at extract concentrations
equivalent to 0.1 nM BP. We show that exposure to low levels of environmental PAH
mixtures more strongly activates these signaling pathways compared to BP alone
suggesting effects due to interactions. Taken together, this is the first study
showing the involvement of MEK4/JNK/AP-1 pathway in regulating the intracellular
stress response after exposure to nanomolar levels of PAHs in environmentalFormasAccepte
Sensitivity of Salmonella YG5161 for detecting PAH-associated mutagenicity in air particulate matter.
The Salmonella/microsome assay is the most used assay for the evaluation of air
particulate matter (PM) mutagenicity and a positive correlation between strain
TA98 responses and benzo[a]pyrene (B[a]P) levels in PM has been found. However,
it seems that the major causes of PM mutagenicity in this assay are the nitro and
oxy-PAHs. Salmonella YG5161, a 30-times more responsive strain to B[a]P has been
developed. To verify if YG5161 strain was sufficiently sensitive to detect
mutagenicity associated with B[a]P mutagenicity, PM samples were collected in
Brazil and Sweden, extracted with toluene and tested in the Salmonella/microsome
microsuspension assay. PAHs and B[a]P were determined and the extracts were
tested with YG5161 and its parental strain TA1538. The extracts were also tested
with YG1041 and its parental strain TA98. For sensitivity comparisons, we tested
B[a]P and 1-nitropyrene (1-NP) using the same conditions. The minimal effective
dose of B[a]P was 155 ng/plate for TA1538 and 7 ng/plate for YG5161. Although the
maximum tested dose, 10 m(3) /plate containing 9 ng of B[a]P in the case of
Brazilian sample, was sufficient to elicit a response in YG5161, mutagenicity was
detected at a dose as low as 1 m(3) /plate (0.9 ng). This is probably caused by
nitro-compounds that have been shown to be even more potent than B[a]P for
YG5161. It seems that the mutagenicity of B[a]P present in PM is not detectable
even with the use of YG5161 unless more efficient separation to remove the
nitro-compounds from the PAH extract is performed.FormasAccepte
Методи управління екологічними ризиками в системі забезпечення економічного розвитку регіону
Метою статті є дослідження методів управління екологічними ризиками в системі забезпечення економічного розвитку регіону
Assessing the effects of global warming and local social and economic conditions on the malaria transmission
Detection of benz[j]aceanthrylene in urban air and evaluation of its genotoxic potential.
Benz[j]aceanthrylene (B[j]A) is a cyclopenta-fused polycyclic aromatic
hydrocarbon with strong mutagenic and carcinogenic effects. We have identified
B[j]A in air particulate matter (PM) in samples collected in Stockholm, Sweden
and in Limeira, Brazil using LC-GC/MS analysis. Determined concentrations ranged
between 1.57 and 12.7 and 19.6-30.2 pg/m(3) in Stockholm and Limeira,
respectively, which was 11-30 times less than benzo[a]pyrene (B[a]P)
concentrations. Activation of the DNA damage response was evaluated after
exposure to B[j]A in HepG2 cells in comparison to B[a]P. We found that
significantly lower concentrations of B[j]A were needed for an effect on cell
viability compared to B[a]P, and equimolar exposure resulted in significant more
DNA damage with B[j]A. Additionally, levels of gammaH2AX, pChk1, p53, pp53, and
p21 proteins were higher in response to B[j]A than B[a]P. On the basis of dose
response induction of pChk1 and gammaH2AX, B[j]A potency was 12.5- and 33.3-fold
higher than B[a]P, respectively. Although B[j]A levels in air were low, including
B[j]A in the estimation of excess lifetime cancer risk increased the risk up to
2-fold depending on which potency factor for B[j]A was applied. Together, our
results show that B[j]A could be an important contributor to the cancer risk of
air PM.FormasAccepte
Hemocompatibility of Silicon-Based Substrates for Biomedical Implant Applications
Silicon membranes with highly uniform nanopore sizes fabricated using microelectromechanical systems (MEMS) technology allow for the development of miniaturized implants such as those needed for renal replacement therapies. However, the blood compatibility of silicon has thus far been an unresolved issue in the use of these substrates in implantable biomedical devices. We report the results of hemocompatibility studies using bare silicon, polysilicon, and modified silicon substrates. The surface modifications tested have been shown to reduce protein and/or platelet adhesion, thus potentially improving biocompatibility of silicon. Hemocompatibility was evaluated under four categories—coagulation (thrombin–antithrombin complex, TAT generation), complement activation (complement protein, C3a production), platelet activation (P-selectin, CD62P expression), and platelet adhesion. Our tests revealed that all silicon substrates display low coagulation and complement activation, comparable to that of Teflon and stainless steel, two materials commonly used in medical implants, and significantly lower than that of diethylaminoethyl (DEAE) cellulose, a polymer used in dialysis membranes. Unmodified silicon and polysilicon showed significant platelet attachment; however, the surface modifications on silicon reduced platelet adhesion and activation to levels comparable to that on Teflon. These results suggest that surface-modified silicon substrates are viable for the development of miniaturized renal replacement systems
Complete motor recovery after acute paraparesis caused by spontaneous spinal epidural hematoma: case report
<p>Abstract</p> <p>Background</p> <p>Spontaneous spinal epidural hematoma is a relatively rare but potentially disabling disease. Prompt timely surgical management may promote recovery even in severe cases.</p> <p>Case presentation</p> <p>We report a 34-year-old man with a 2-hour history of sudden severe back pain, followed by weakness and numbness over the bilateral lower limbs, progressing to intense paraparesis and anesthesia. A spinal magnetic resonance imaging scan was performed and revealed an anterior epidural hematoma of the thoracic spine. He underwent an emergency decompression laminectomy of the thoracic spine and hematoma evacuation. Just after surgery, his lower extremity movements improved. After 1 week, there was no residual weakness and ambulation without assistance was resumed, with residual paresthesia on the plantar face of both feet. After 5 months, no residual symptoms persisted.</p> <p>Conclusions</p> <p>The diagnosis of spontaneous spinal epidural hematoma must be kept in mind in cases of sudden back pain with symptoms of spinal cord compression. Early recognition, accurate diagnosis and prompt surgical treatment may result in significant improvement even in severe cases.</p
Use of linear mixed models for genetic evaluation of gestation length and birth weight allowing for heavy-tailed residual effects
<p>Abstract</p> <p>Background</p> <p>The distribution of residual effects in linear mixed models in animal breeding applications is typically assumed normal, which makes inferences vulnerable to outlier observations. In order to mute the impact of outliers, one option is to fit models with residuals having a heavy-tailed distribution. Here, a Student's-<it>t </it>model was considered for the distribution of the residuals with the degrees of freedom treated as unknown. Bayesian inference was used to investigate a bivariate Student's-<it>t </it>(BS<it>t</it>) model using Markov chain Monte Carlo methods in a simulation study and analysing field data for gestation length and birth weight permitted to study the practical implications of fitting heavy-tailed distributions for residuals in linear mixed models.</p> <p>Methods</p> <p>In the simulation study, bivariate residuals were generated using Student's-<it>t </it>distribution with 4 or 12 degrees of freedom, or a normal distribution. Sire models with bivariate Student's-<it>t </it>or normal residuals were fitted to each simulated dataset using a hierarchical Bayesian approach. For the field data, consisting of gestation length and birth weight records on 7,883 Italian Piemontese cattle, a sire-maternal grandsire model including fixed effects of sex-age of dam and uncorrelated random herd-year-season effects were fitted using a hierarchical Bayesian approach. Residuals were defined to follow bivariate normal or Student's-<it>t </it>distributions with unknown degrees of freedom.</p> <p>Results</p> <p>Posterior mean estimates of degrees of freedom parameters seemed to be accurate and unbiased in the simulation study. Estimates of sire and herd variances were similar, if not identical, across fitted models. In the field data, there was strong support based on predictive log-likelihood values for the Student's-<it>t </it>error model. Most of the posterior density for degrees of freedom was below 4. Posterior means of direct and maternal heritabilities for birth weight were smaller in the Student's-<it>t </it>model than those in the normal model. Re-rankings of sires were observed between heavy-tailed and normal models.</p> <p>Conclusions</p> <p>Reliable estimates of degrees of freedom were obtained in all simulated heavy-tailed and normal datasets. The predictive log-likelihood was able to distinguish the correct model among the models fitted to heavy-tailed datasets. There was no disadvantage of fitting a heavy-tailed model when the true model was normal. Predictive log-likelihood values indicated that heavy-tailed models with low degrees of freedom values fitted gestation length and birth weight data better than a model with normally distributed residuals.</p> <p>Heavy-tailed and normal models resulted in different estimates of direct and maternal heritabilities, and different sire rankings. Heavy-tailed models may be more appropriate for reliable estimation of genetic parameters from field data.</p
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