Long-term effects of developmental exposure to di-n-butyl-phthalate (DBP) on rat prostate: Proliferative and inflammatory disorders and a possible role of androgens

In the present study we evaluated the toxic effects on the male adult rat prostate of DBP exposure during fetal and lactational periods, because although many studies have addressed the influence of phthalates on the male reproductive system, only a few have discussed their possible effects on prostate development. Pregnant females were distributed into two experimental groups: Control (C) and Treated (T). The females of the T group received DBP (100 mg/kg, by gavage) from gestation day 12 to postnatal day 21, while C rats received the vehicle (corn oil). In adulthood (90 days old), the animals were euthanized. The serum and testicular testosterone levels were measured. Ventral prostate was removed and weighed. Distal segment fragments of the ventral prostate were fixed and processed for histochemistry and immunohistochemistry to detect androgen receptor (AR) and Ki67 antigens. Protein extraction from ventral prostate fragments was performed for AR immunoblotting and Gelatin zymography for MMP-2 and MMP-9 (MMP, metalloproteinase). Stereological and histopathological analyses were also performed. Serum and testicular testosterone levels and prostate weight were comparable between groups. In the T group the relative proportions (%) of epithelial (C=32.86; T=42.04*) and stromal (C=21.61; T=27.88*) compartments were increased, while the luminal compartment was decreased (C=45.54; T=30.08*), *p < 0.05. In T, disseminated inflammatory infiltrate in the stroma, associated or not with epithelial dysplasia and PIN (Prostatic Intraepithelial Neoplasia), was observed. Increases in AR expression, proliferation index and metalloproteinase 9 (MMP-9) activity were noted in T animals. In some T animals, collagen fibrils accumulated adjacent to the epithelium. As far as we are aware, this is the first report in the literature showing that phthalates could play a role in proliferative and inflammatory disorders of the rat prostate. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Exposure to lead exacerbates dental fluorosis

Aim: Our aim was to test: the hypothesis that co-exposure to lead and fluoride alter the severity of enamel fluorosis. Materials and methods: Wistar rats were allocated in four groups: control, and 3 groups that received water containing 100 ppm of fluoride (F), 30 ppm of lead (Pb), or 100 ppm of F and 30 ppm of Pb (F + Pb) from the beginning of gestation. Enamel analysis and F and Pb determinations in enamel, dentine, and bone were performed in 81-day-old animals. Fluorosis was quantified using a new fluorosis index based on the identification of incisor enamel defects (white bands and white islets, representing hypomineralization, and cavities) weighted according to their severity and quantity. Hypomineralization was validated histopathologically by polarizing microscopy and microradiography. Scores were given by two blinded calibrated examiners (intra and interexaminer kappa values were 0.8 and 0.86, respectively). Results: The control and the Pb groups presented normal enamel. The F + Pb group presented more severe enamel defects compared with the F group (P < 0.0001). Conclusions: This study shows that lead exacerbates dental fluorosis in rodents, suggesting that co-exposure to lead may affect the degree of fluorosis. (C) 2011 Elsevier Ltd. All rights reserved.

Exposure to ambient levels of particles emitted by traffic worsens emphysema in mice

Objectives: We investigated effects of chronic exposure (2 months) to ambient levels of particulate matter (PM) on development of protease-induced emphysema and pulmonary remodeling in mice. Methods: Balb/c mice received nasal drop of either papain or normal saline and were kept in two exposure chambers situated in an area with high traffic density. One of them received ambient air and the other had filters for PM. Results: mean concentration of PM10 was 2.68 +/- 0.38 and 33.86 +/- 2.09 mu g/m(3), respectively, in the filtered and ambient air chambers (p<0.001). After 2 months of exposure, lungs from papain-treated mice kept in the chamber with ambient air presented greater values of mean linear intercept, an increase in density of collagen fibers in alveolar septa and in expression of 8-isoprostane (p = 0.002, p < 0.05 and p = 0.002, respectively, compared to papain-treated mice kept in the chamber with filtered air). We did not observe significant differences between these two groups in density of macrophages and in amount of cells expressing matrix metalloproteinase-12. There were no significant differences in saline-treated mice kept in the two chambers. Conclusions: We conclude that exposure to urban levels of PM worsens protease-induced emphysema and increases pulmonary remodeling. We suggest that an increase in oxidative stress induced by PM exposure influences this response. These pulmonary effects of PM were observed only in mice with emphysema. (C) 2009 Elsevier Inc. All rights reserved.

Prolonged exposure to palmitate impairs fatty acid oxidation despite activation of AMP-activated protein kinase in skeletal muscle cells

The aim of this study was to investigate the chronic effects of palmitate on fatty acid (FA) oxidation, AMPK/ACC phosphorylation/activation, intracellular lipid accumulation, and the molecular Mechanisms involved in these processes in skeletal muscle cells. Exposure of L6 myotubes for 8 h to 200, 400, 600, and 800 mu M of palmitate did rot affect cel viability but significantly reduced FA oxidation by similar to 26.5%, similar to 43.5%, similar to 50%, and similar to 47%, respectively. Interestingly, this occurred despite significant increases in AMPK (similar to 2.5-fold) and ACC (similar to 3-fold) phosphorylation and in malonyl-CoA decarboxylase activity (similar to 38-60%). Low concentrations of palmitate (50-100 mu M) caused an increase (similar to 30%) in CPT-I activity. However, as the concentration of palmitate increased, CPT-I activity decreased by similar to 32% after exposure for 8 h to 800 mu M of palmitate. Although FA uptake was reduced (similar to 35%) in cells exposed to increasing, palmitate concentrations, intracellular lipid accumulation increased in a dose-dependent manner, reaching values similar to 2.3-, similar to 3-, and 4-fold higher than control in muscle cells exposed to 400, 600, and 800 mu M palmitate, respectively. Interestingly, myotubes exposed to 400 mu M of palmitate for 1h increased basal glucose uptake and glycogen synthesis by similar to 40%. However, as time of incubation in the presence of palmitate progressed from 1 to 8h, these increases were abolished and a time-dependent inhibition of insulin-stimulated glucose uptake (similar to 65%) and glycogen synthesis (30%) was observed in myotubes. These findings may help explain the dysfunctional adaptations that occur in glucose and FA Metabolism in skeletal muscle under conditions of chronically elevated circulating levels of non-esterified FAs. Such as in obesity and Type 2 Diabetes.

Transcriptional regulation of the Na(+)/H(+) exchanger NHE3 by chronic exposure to angiotensin II in renal epithelial cells

Angiotensin II (Ang II) exerts an acute bimodal effect on proximal tubule NHE3: while low doses stimulate the exchanger, high doses inhibit it. In the present study, we have investigated the chronic effects of Ang II on NHE3 expression and transcriptional regulation. Treatment of a tubular epithelial cell line, OKP, with Ang II 10(-11) M significantly increased NHE protein expression and mRNA levels, without evidence of bimodal effect. No change in mRNA half-life was detected, but transient transfection studies showed a significant increase in NHE3 promoter activity. Binding sites for Sp1/Egr-1 and AP2 transcription factors of the NHE3 proximal promoter were mutated and we observed that the Sp1/Egr-1 binding site integrity is necessary for Ang II stimulatory effects. Inhibition of cytochrome P450, PI3K, PKA and MAPK pathways prevented the Ang II stimulatory effect on the NHE3 promoter activity. Taking all the results together, our data reveal that chronic Ang II treatment exerts a stimulatory effect on NHE3 expression and promoter activity. The Ang II up-regulation of the NHE3 promoter activity appears to involve the Sp1/Egr-1 binding site and the interplay of several intracellular signaling pathways. (C) 2011 Elsevier Inc. All rights reserved.

Occupational exposure to radon and natural gamma radiation in the La Carolina, a former gold mine in San Luis Province, Argentina

Radon and gamma radiation level measurements were carried out inside the La Carolina mine, one of the oldest gold mining camps of southern South America, which is open for touristic visits nowadays. CR-39 track-etch detectors and thermoluminescent dosimeters of natural CaF(2) and LiF TLD-100 were exposed at 14 points along the mine tunnels in order to estimate the mean (222)Rn concentration and the ambient dose equivalent during the summer season (November 2008 to February 2009). The values for the (222)Rn concentration at each monitoring site ranged from 1.8 +/- 0.1 kBq m(-3) to 6.0 +/- 0.5 kBq m(-3), with a mean value of 4.8 kBq m(-3), indicating that these measurements exceed in about three times the upper action level recommended by ICRP for workplaces. The correlations between radon and gamma radiation levels inside the mine were also investigated. Effective doses due to (222)Rn and gamma rays inside the mine were determined, resulting in negligible values to tourists. Considering the effective dose to the mine tourist guides, values exceeding 20 mSv of internal contribution to the effective doses can be reached, depending on the number of working hours inside the mine. (C) 2009 Elsevier Ltd. All rights reserved.

Association of dental enamel lead levels with risk factors for environmental exposure

OBJECTIVE: To analyze household risk factors associated with high lead levels in surface dental enamel. METHODS: A cross-sectional study was conducted with 160 Brazilian adolescents aged 14-18 years living in poor neighborhoods in the city of Bauru, southeastern Brazil, from August to December 2008. Body lead concentrations were assessed in surface dental enamel acid-etch microbiopsies. Dental enamel lead levels were measured by graphite furnace atomic absorption spectrometry and phosphorus levels were measured by inductively coupled plasma optical emission spectrometry. The parents answered a questionnaire about their children's potential early (05 years old) exposure to well-known lead sources. Logistic regression was used to identify associations between dental enamel lead levels and each environmental risk factor studied. Social and familial covariables were included in the models. RESULTS: The results suggest that the adolescents studied were exposed to lead sources during their first years of life. Risk factors associated with high dental enamel lead levels were living in or close to a contaminated area (OR = 4.49; 95% CI: 1.69;11.97); and member of the household worked in the manufacturing of paints, paint pigments, ceramics or batteries (OR = 3.43; 95% CI: 1.31;9.00). Home-based use of lead-glazed ceramics, low-quality pirated toys, anticorrosive paint on gates and/or sale of used car batteries (OR = 1.31; 95% CI: 0.56;3.03) and smoking (OR = 1.66; 95% CI: 0.52;5.28) were not found to be associated with high dental enamel lead levels. CONCLUSIONS: Surface dental enamel can be used as a marker of past environmental exposure to lead and lead concentrations detected are associated to well-known sources of lead contamination.

In vitro fertilization, embryo development, and cell lineage segregation after pre- and/or postnatal exposure of female mice to ambient fine particulate matter

Objective: To evaluate effects of pre- and/or postnatal exposure to ambient fine particulate matter on fertilization, embryo development, and cell lineage segregation in preimplantation blastocysts using the IVF mouse model. Design: Animal model. Setting: Academic institution. Animal(S): Six-week-old, superovulated mice. Intervention(s): Pre- and postnatal exposure to filtered air (FA-FA), filtered-ambient air (FA-AA), or ambient air (AA-AA) in exposure chambers 24 hours a day for 9 weeks. Main Outcome Measure(S): Gestation length, litter size, sex ratio, ovarian response to superovulation, fertilization rate, embryo development, blastocyst and hatching rates, total cell count, and proportion of cell allocation to inner-cell mass (ICM) and trophectoderm (TE). Result(S): Gestation length, litter size and birth weight, live-birth index, and sex ratio were similar among exposure groups. Ovarian response was not affected by the exposure protocol. A multivariate effect for pre- and/or postnatal exposure to ambient fine particulate matter on IVF, embryo development, and blastocyst differential staining was found. Cell counts in ICM and ICM/TE ratios in blastocysts produced in the FA-FA protocol were significantly higher than in blastocysts produced in the FA-AA and AA-AA protocols. No difference in total cell count was observed among groups. Conclusion(S): Our study suggests that exposure to ambient fine particulate matter may negatively affect female reproductive health by disrupting the lineage specification at the blastocyst stage without interfering in early development of the mouse embryo. (Fertil Steril (R) 2009;92:1725-35. (C) 2009 by American Society for Reproductive Medicine.)

Analysis and risk estimates to workers of Brazilian granitic industries and sandblasters exposed to respirable crystalline silica and natural radionuclides

Occupational exposure to respirable crystalline silica and to radiation emitted by natural radionuclides present both in rocks and sands was studied in the Brazilian extractive process and granite product manufacture. Respirable airborne dust samples were collected in working environments, where workers perform different tasks with distinct commercial granites types, and also in places where sandblasters work with sands from different origins. The free crystalline silica contents were determined using X-ray diffraction of the respirable particulate fraction of each sample. Dust samples from granite cutting and sandblasting ambient had the natural radionuclides concentrations measured by gamma spectrometry. Dust concentrations in the workplaces were quite variable, reaching values up to 10 times higher than the respirable particle mass threshold limit value (TLV) set by the American Conference for Governmental Industrial Hygienists of 3 mg m(-3). Also the free crystalline silica concentrations were high. reaching values up to 48 times the TLV of 0.025 mg m(-3). Additionally, our results suggest that the risk of radiation-induced cancer in the granite or marble industries is negligible. However, the combined exposure to dust, gamma radiation, and radon daughter products could result in the enhancement of lung cancer risks associated to sandblasting activities. (C) 2010 Elsevier Ltd. All rights reserved.

Incidence and risk factors of aplastic anemia in Latin American countries: the LATIN case-control study

Background Associations between aplastic anemia and numerous drugs, pesticides and chemicals have been reported. However, at least 50% of the etiology of aplastic anemia remains unexplained. Design and Methods This was a case-control, multicenter, multinational study, designed to identify risk factors for agranulocytosis and aplastic anemia. The cases were patients with diagnosis of aplastic anemia confirmed through biopsy or bone marrow aspiration, selected through an active search of clinical laboratories, hematology clinics and medical records. The controls did not have either aplastic anemia or chronic diseases. A total of 224 patients with aplastic anemia were included in the study, each case was paired with four controls, according to sex, age group, and hospital where the case was first seen. Information was collected on demographic data, medical history, laboratory tests, medications, and other potential risk factors prior to diagnosis. Results The incidence of aplastic anemia was 1.6 cases per million per year. Higher rates of benzene exposure (>= 30 exposures per year) were associated with a greater risk of aplastic anemia (odds ratio, OR: 4.2; 95% confidence interval, CI: 1.82-9.82). Individuals exposed to chloramphenicol in the previous year had an adjusted OR for aplastic anemia of 8.7 (CI: 0.87-87.93) and those exposed to azithromycin had an adjusted OR of 11.02 (CI 1.14-108.02). Conclusions The incidence of aplastic anemia in Latin America countries is low. Although the research study centers had a high coverage of health services, the underreporting of cases of aplastic anemia in selected regions can be discussed. Frequent exposure to benzene-based products increases the risk for aplastic anemia. Few associations with specific drugs were found, and it is likely that some of these were due to chance alone.

How much do smoking and alcohol consumption explain socioeconomic inequalities in head and neck cancer risk?

Background A higher burden of head and neck cancer has been reported to affect deprived populations. This study assessed the association between socioeconomic status and head and neck cancer, aiming to explore how this association is related to differences of tobacco and alcohol consumption across socioeconomic strata. Methods We conducted a case-control study in Sao Paulo, Brazil (1998-2006), including 1017 incident cases of oral, pharyngeal and laryngeal cancer, and 951 sex- and age-matched controls. Education and occupation were distal determinants in the hierarchical approach; cumulative exposure to tobacco and alcohol were proximal risk factors. Outcomes of the hierarchical model were compared with fully adjusted ORs. Results Individuals with lower education (OR 2.27; 95% CI 1.61 to 3.19) and those performing manual labour (OR 1.55; 95% CI 1.26 to 1.92) had a higher risk of disease. However, 54% of the association with lower education and 45% of the association with manual labour were explained by proximal lifestyle exposures, and socioeconomic status remained significantly associated with disease when adjusted for smoking and alcohol consumption. Conclusions Socioeconomic differences in head and neck cancer are partially attributable to the distribution of tobacco smoking and alcohol consumption across socioeconomic strata. Additional mediating factors may explain the remaining variation of socioeconomic status on head and neck cancer.

The Controllership Relevance or Risk Management in non-Financial Companies: a study of risk managers` and controllers` perceptions

The purpose of this study is to analyze the Controllership relevance as support risk management in non-financial companies. Risk management is a widely discussed and disseminated subject amongst financial institutions. It is obvious that economic uncertainties and, consequently, prevention and. control must also exist in non-financial companies. To enable managers to take safe-decisions, it is essential for them to be able to count on instrumental support that provides timely and adequate information, to ensure lower levels of mistakes and risk exposure. However, discussion concerning risk management in non-financial companies is still in its early stages in Brazil. Considering this gap, this study aims at assessing how Controllership has been acting in? companies under the insight of risk and how it can contribute to risk management in non-financial companies. To achieve the proposed goal, a field research was. carried-out with non-financial companies that are located in the city Sao Paulo and listed in the Sao Paulo Stock Exchange (Bovespa). The research was carried out using questionnaires, which were sent do Risk Officers and Controllers of those companies with the purpose of evaluating their perception on the subject. The results,of the research allow us to conclude that Controllership offers support to risk management, through information that contributes to the mitigation of the risks in non-financial companies.

Prevalence and Risk of Asthma Symptoms Among Firefighters in Sao Paulo, Brazil: A Population-Based Study

The firefighters are at increased risk of respiratory disease as a result of exposure to smoke and dust. The aim of this study was to determine the prevalence and risk associated with respiratory symptoms among city firefighters in Sao Paulo, Brazil. Methods A cross-sectional study utilizing the European Community Respiratory Health Survey (ECRHS) questionnaire was administered to firefighters and police officers, in order to evaluate their respiratory symptoms. Results Complete respiraton, data were obtained from 1,235 firefighters and 1,839 police officers. Among the firefighters, there were 55.5% never-smokers, 22.4% current smokers and 18.2% former smokers (P < 0.05). Among the police officers, there were 63.4%, 18.6%, and 9.6% who were never-smokers, current smokers and former smokers (P < 0.05), respectively. Compared to police, firefighters experienced an increase in wheezing [OR = 1.63 (95% CI: 1.43-1.87)], wheezing with breathlessness [OR = 1.34 (95% CI: 1.10-1.64)], wheezing without a cold [OR = 1.60 (95% CI: 1.32-1.95)], waking with tightness in the chest [OR = 1.20 (95% CI: 1.02-1.42)], and rhinitis [OR = 1.12 (95% CI: 1.03-1.22)]. The prevalence of adult-onset asthma in never-smokers was 9.3% and 6.7% for firefighters and police officers [OR = 1.23 (95% CI: 1.01-1.56)]. All independent association was observed between years employed, smoking, history of rhinitis, and work as a firefighter and respiratory, and nasal symptoms. We observed a high prevalence of asthma-like symptoms in firefighters who presented respiratory symptoms beginning immediately after firefighting. Conclusion These results suggest that the prevalence of respiratory symptoms and asthma in firefighters is higher than those in police officers. Work-as a firefighter, rhinitis and vears employed were risk factors for respiratory,symptoms of asthma. Am. J. Ind. Med. 52:261 269, 2009. (C) 2008 Wiley-Liss, Inc.

TP53 and EGFR mutations in combination with lifestyle risk factors in tumours of the upper aerodigestive tract from South America

Cancers of the upper aerodigestive tract [(UADT): oral cavity, pharynx, larynx and oesophagus] have high incidence rates in some parts of South America. Alterations in the TP53 gene are common in these cancers. In our study, we have estimated the prevalence and patterns of TP53 mutations (exons 4-10) in 236 UADT tumours from South America in relation to lifestyle risk factors, such as tobacco smoking and alcohol drinking. Moreover, we have conducted a pilot study of EGFR mutations (exons 18-21) in 45 tumours from the same population. TP53 mutation prevalence was high: 59% of tumours were found to carry mutant TP53. We found an association between TP53 mutations and tobacco smoking and alcohol drinking. The mutation rate increased from 38% in never-smokers to 66% in current smokers (P-value for trend = 0.09). G:C > T:A transversions were found only in smokers (15%). Alcohol drinkers carried more G:C > A:T transitions (P = 0.08). Non-exposed individuals were more probable to carry G:C > A:T transitions at CpG sites (P = 0.01 for never-smokers and P < 0.001 for never-drinkers). EGFR mutations were found in 4% of cases. Inactivation of TP53 by mutations is a crucial molecular event in the UADT carcinogenesis and it is closely related to exposure to lifestyle risk factors. EGFR mutations do not appear to be a common event in UADT carcinogenesis in this population.

Marijuana Smoking and the Risk of Head and Neck Cancer: Pooled Analysis in the INHANCE Consortium

Background: Marijuana contains carcinogens similar to tobacco smoke and has been suggested by relatively small studies to increase the risk of head and neck cancer (HNC). Because tobacco is a major risk factor for HNC, large studies with substantial numbers of never tobacco users could help to clarify whether marijuana smoking is independently associated with HNC risk. Methods: We pooled self-reported interview data on marijuana smoking and known HNC risk factors on 4,029 HNC cases and 5,015 controls from five case-control studies within the INHANCE Consortium. Subanalyses were conducted among never tobacco users (493 cases and 1,813 controls) and among individuals who did not consume alcohol or smoke tobacco (237 cases and 887 controls). Results: The risk of HNC was not elevated by ever marijuana smoking [odds ratio (OR), 0.88; 95% confidence intervals (95% Cl), 0.67-1.16], and there was no increasing risk associated with increasing frequency, duration, or cumulative consumption of marijuana smoking. An increased risk of HNC associated with marijuana use was not detected among never tobacco users (OR, 0.93; 95% Cl, 0.63-1.37; three studies) nor among individuals who did not drink alcohol and smoke tobacco (OR, 1.06; 95% Cl, 0.47-2.38; two studies). Conclusion: Our results are consistent with the notion that infrequent marijuana smoking does not confer a risk of these malignancies. Nonetheless, because the prevalence of frequent marijuana smoking was low in most of the contributing studies, we could not rule out a moderately increased risk, particularly among subgroups without exposure to tobacco and alcohol. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1544-51)