Biological monitoring of chemical exposure : toxicokinetic differences due to age and sex

Human biomonitoring is a widely used method in the assessment of occupational exposure to chemical substances and recommended biological limits are published periodically for interpretation and decision-making. However, it is increasingly recognized that a large variability is associated with biological monitoring, making interpretation less efficient than assumed. In order to improve the applicability of biological monitoring, specific factors responsible for this variability should be identified and their contribution quantified. Among these factors, age and sex are easily identifiable, and present knowledge about pharmaceutical chemicals suggests that they play an important role on the toxicokinetics of occupational chemical agents, and therefore on the biological monitoring results.The aim of the present research project was to assess the influence of age and sex on biological indicators corresponding to organic solvents. This has been done experimentally and by toxicokinetic computer simulation. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile.Age differences were identified by numerical simulations using a general toxicokinetic model from a previous study which was applied to 14 chemicals, representing 21 specific biological entities, with, among others, toluene, phenol, lead and mercury. These models were runn with the modified parameters, indicating in some cases important differences due to age. The expected changes are mostly of the order of 10-20 %, but differences up to 50 % were observed in some cases. These differences appear to depend on the chemical and on the biological entity considered.Sex differences were quantified by controlled human exposures, which were carried out in a 12 m3 exposure chamber for three organic solvents separately: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. The human volunteer groups were composed 12 of ten young men and fifteen young women, the latter subdivided into those with and without hormonal contraceptive. They were exposed during six hours at rest and at half of the threshold limit value. The kinetics of the parent compounds (organic volatiles) and their metabolite(s) were followed in blood, urine and expired air over time. Analyses of the solvent and their metabolites were performed by using headspace gas chromatography, CYP2E1 genotypes by using PCR-based RFLP methods. Experimental data were used to calibrate the toxicokinetic models developed for the three solvents. The results obtained for the different biomarkers of exposure mainly showed an effect on the urinary levels of several biomarkers among women due to the use of hormonal contraceptive, with an increase of about 50 % in the metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Simulations showed that it is possible to use simple toxicokinetic tools in order to predict internal exposure when exposed to organic solvents. Our study suggests that not only physiological differences but also exogenous sex hormones could influence CYP2E1 enzyme activity. The variability among the urinary biological indicators levels gives evidence of an interindividual susceptibility, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Sex differences in atheroma burden and endothelial function in patients with early coronary atherosclerosis.

AIMS: Women and men have different clinical presentations and outcomes in coronary artery disease (CAD). We tested the hypothesis that sex differences may influence coronary atherosclerotic burden and coronary endothelial function before development of obstructive CAD. METHODS AND RESULTS: A total of 142 patients (53 men, 89 women; mean +/- SD age, 49.3 +/- 11.7 years) with early CAD simultaneously underwent intravascular ultrasonography and coronary endothelial function assessment. Atheroma burden in the left main and proximal left anterior descending (LAD) arteries was significantly greater in men than women (median, 23.0% vs. 14.1%, P = 0.002; median, 40.1% vs. 29.3%, P = 0.001, respectively). Atheroma eccentricity in the proximal LAD artery was significantly higher in men than women (median, 0.89 vs. 0.80, P = 0.04). The length of the coronary segments with endothelial dysfunction was significantly longer in men than women (median, 39.2 vs. 11.1 mm, P = 0.002). In contrast, maximal coronary flow reserve was significantly lower in women than men (2.80 vs. 3.30, P < 0.001). Sex was an independent predictor of atheroma burden in the left main and proximal LAD arteries (both P < 0.05) by multivariate analysis. CONCLUSION: Men have greater atheroma burden, more eccentric atheroma, and more diffuse epicardial endothelial dysfunction than women. These results suggest that men have more severe structural and functional abnormalities in epicardial coronary arteries than women, even in patients with early atherosclerosis, which may result in the higher incidence rates of CAD and ST-segment myocardial infarction in men than women.

Differences in ureide and amino acid content of water stressed soybean inoculated with Bradyrhizobium japonicum and B. elkanii

The objective of this work was to study the response to water stress of a drought sensitive soybean cultivar inoculated with Bradyrhizobium japonicum (strain CB1809, Semia 586) and B. elkanii (strain 29W, Semia 5019). CB1809 nodulated plants produced a significantly higher root fraction (19%) than 29W (14.6%). Plants inoculated with CB1809 produced less nodules and accumulated more nitrogen than those inoculated with 29W. In general, low amounts of ureides in nodules were found in watered plants inoculated with either CB1809 or 29W strains, but those levels were five-fold increased in stressed plants inoculated with CB1809. Nodules formed by strain CB1809 had aspartate and glutamate as major amino acids, while those formed by 29W had glutamate, asparagine and alanine. In nodules of plants inoculated with CB1809 aspartate showed the highest accumulation (5 µmol g-1); in stressed plants this amino acid reached a value of 26 µmol g-1, and asparagine was not detected. Nodules formed by the strain 29W accumulated 1 µmol g-1 of aspartate, whether plants were stressed or not. Asparagine was the major amino acid found in nodules from watered plants (6 µmol g-1) and the amount of this amino acid was six-fold increased when plants were water stressed.

Plants of an Eucalyptus clone damaged by Scolytidae and Platypodidae (Coleoptera)

Species of Scolytidae and Platypodidae were evaluated in a plantation using a clone of Eucalyptus grandis x Eucalyptus urophylla in the State of Minas Gerais, Brazil. Wood disks with galleries were taken from 15 eucalyptus trees between 0.5 and 1.5 m height. After collection, all trees attacked were burned. Woodborers obtained from these disks were identified as Premnobius cavipennis, Premnobius ambitiosus, Dryocoetoides cristatus (Coleoptera: Scolytidae) and Euplatypus parallelus (Coleoptera: Platypodidae). This is the first report of D. cristatus, a Brazilian native species, damaging eucalyptus, which shows its adaptation to this plant.

Differences in aerobic fitness and lifestyle characteristics in preschoolers according to their weight status and sports club participation.

Objective: This study assesses differences in adiposity, aerobic fitness, and lifestyle characteristics in preschoolers according to their weight status and sports club (SC) participation. Method: As part of the Ballabeina study, 600 randomly selected preschoolers (mean age 5.1 ± 0.6 years; 50.2% girls) were analyzed. Body composition was measured by bioelectrical impedance, aerobic fitness by the 20-meter shuttle run test, and physical activity by accelerometers. Eating habits, media use, and SC participation were assessed by questionnaires. Results: Overweight children (Swiss national percentiles) and children not participating in SC had both lower aerobic fitness and higher % body fat compared to their respective counterparts (all p ≤ 0.028). In addition, children not participating in SC were less physically active, had more media use, and ate less healthy compared to children participating in SC (all p ≤ 0.023). Controlling for parental sociocultural determinants attenuated differences in % body fat, in physical activity, and in eating habits. Conclusion: Aerobic fitness differs both according to weight status and SC participation in preschoolers. Furthermore, in view of the many differences in lifestyle behaviors, SC participation at this age could represent a more discriminatory indicator of healthy lifestyle characteristics than weight status.

Differences of Functional Connectivity Brain Network in Emotional Judgment

Using combined emotional stimuli, combining photos of faces and recording of voices, we investigated the neural dynamics of emotional judgment using scalp EEG recordings. Stimuli could be either combioned in a congruent, or a non-congruent way.. As many evidences show the major role of alpha in emotional processing, the alpha band was subjected to be analyzed. Analysis was performed by computing the synchronization of the EEGs and the conditions congruent vs. non-congruent were compared using statistical tools. The obtained results demonstrate that scalp EEG ccould be used as a tool to investigate the neural dynamics of emotional valence and discriminate various emotions (angry, happy and neutral stimuli).

The EuroSIDA study: Regional differences in the HIV-1 epidemic and treatment response to antiretroviral therapy among HIV-infected patients across Europe--a review of published results.

EuroSIDA is a pan-European observational study that follows 14,265 HIV-infected patients from 31 European countries, Israel and Argentina, of which 2,560 are patients from eastern Europe (EE). The study group has performed several analyses addressing regional differences in the HIV-epidemic across Europe, where all countries were divided into five regions: south, west central, north, east central Europe and EE. Significant regional differences in patients' characteristics and pattern of AIDS diagnoses were documented. More patients from EE were diagnosed with tuberculosis compared to other regions. Significantly fewer HIV-infected patients in EE, who fulfilled the criteria for starting combination antiretroviral therapy (cART), actually received cART as compared with other regions of Europe. Those, receiving cART in EE had a lower initial virologic response rate irrespectively of the regimen used, although it has improved within years. Besides, treatment failure was more common in this region. Thus, improvements in the clinical management of HIV patients in EE are urgently needed. Strategies include creating scientific collaborations for HIV clinicians as well as teaching clinicians about the most advanced HIV management at clinically oriented courses held in eastern Europe.

Wound-healing gene family expression differences between fetal and foreskin cells used for bioengineered skin substitutes.

For tissue engineering, several cell types and tissues have been proposed as starting material. Allogenic skin products available for therapeutic usage are mostly developed with cell culture and with foreskin tissue of young individuals. Fetal skin cells offer a valuable solution for effective and safe tissue engineering for wounds due to their rapid growth and simple cell culture. By selecting families of genes that have been reported to be implicated in wound repair and particularly for scarless fetal wound healing including transforming growth factor-beta (TGF-beta) superfamily, extracellular matrix, and nerve/angiogenesis growth factors, we have analyzed differences in their expression between fetal skin and foreskin cells, and the same passages. Of the five TGF-beta superfamily genes analyzed by real-time reverse transcription-polymerase chain reaction, three were found to be significantly different with sixfold up-regulated for TGF-beta2, and 3.8-fold for BMP-6 in fetal cells, whereas GDF-10 was 11.8-fold down-regulated. For nerve growth factors, midkine was 36-fold down-regulated in fetal cells, and pleiotrophin was 4.76-fold up-regulated. We propose that fetal cells present technical and therapeutic advantages compared to foreskin cells for effective cell-based therapy for wound management, and overall differences in gene expression could contribute to the degree of efficiency seen in clinical use with these cells.

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging.

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19-75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration.

Métodos indiretos de estimação da cobertura de dossel em povoamentos de clone de eucalipto

O objetivo deste trabalho foi avaliar o potencial de uso de fotografias digitais na estimação do índice de cobertura de dossel (ICD), em substituição ao índice de área foliar (IAF). Fotografias digitais de 640x480 e de 1.280x960 pixels foram processadas por meio dos aplicativos Erdas, Gap Light Analyzer e Sidelook. O IAF, estimado com o LAI-2000, e as fotografias digitais foram obtidos aos 81 e 93 meses de idade, em povoamento de clone de eucalipto submetido à desrama e ao desbaste. Foram observadas correlações significativas entre IAF e ICD, e as fotografias com maiores dimensões permitiram maior diferenciação entre céu e dossel. O ICD, obtido pela classificação das fotografias com o aplicativo Sidelook, apresentou correlação mais elevada com o IAF, em relação ao obtido com o Erdas e o Gap Light Analyzer. Esses resultados indicam que fotografias digitais podem ser utilizadas para estimar o ICD de povoamentos florestais.

Flight energetics in relation to sexual differences in the mating behaviour of a mayfly, Siphlonurus aestivalis

Mayflies (Ephemeroptera) are known to have short adult life-spans. Adults are unable to feed, and they utilize reserves stored during their aquatic larval stage. Energy reserves (fat, glycogen, and free sugars) of mature larvae, subimagoes and imagoes of both sexes of Siphlonurus aestivalis Eaton were compared. All the stages of both sexes had low glycogen and free sugar contents, and the only significant change occurred during the transformation of the mature larva to subimago when almost all the reserves of free sugars were used up. Glycogen and free sugars may serve as energy sources permitting individuals to swim and fly out of the water during emergence. Fat made up most of the energy reserves of mature larvae and was the main source of energy used during the final development of both sexes. Young adult males had high fat reserves which they used as a source of energy for their swarming flights. In contrast, females did not seem to use a significant amount of fat for flight. This difference is probably related to the different mating strategies of the sexes in this species. Males perform long flights waiting for females, whereas females perform only brief flights to mate and reproduce.

Recovery of a persistent Canine distemper virus expressing the enhanced green fluorescent protein from cloned cDNA.

Wild-type A75/17-Canine distemper virus (CDV) is a highly virulent strain, which induces a persistent infection in the central nervous system (CNS) with demyelinating disease. Wild-type A75/17-CDV, which is unable to replicate in cell lines to detectable levels, was adapted to grow in Vero cells and was designated A75/17-V. Sequence comparison between the two genomes revealed seven nucleotide differences located in the phosphoprotein (P), the matrix (M) and the large (L) genes. The P gene is polycistronic and encodes two auxiliary proteins, V and C, besides the P protein. The mutations resulted in amino acid changes in the P and V, but not in the C protein, as well as in the M and L proteins. Here, a rescue system was developed for the A75/17-V strain, which was shown to be attenuated in vivo, but retains a persistent infection phenotype in Vero cells. In order to track the recombinant virus, an additional transcription unit coding for the enhanced green fluorescent protein (eGFP) was inserted at the 3' proximal position in the A75/17-V cDNA clone. Reverse genetics technology will allow us to characterize the genetic determinants of A75/17-V CDV persistent infection in cell culture.

Degree of previous cutting in explaining the differences in diameter distributions between mature managed and natural Norway spruce forests

Abstract