TERT-independent telomere elongation and shelterin dysregulation after pulmonary exposure to stainless-steel welding fume in-vivo.

Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.

Cadmium and Cadmium/Zinc Ratios and Tobacco-Related Morbidities.

Metals are one of five major categories of carcinogenic or toxic constituents in tobacco and tobacco smoke. Cadmium is highly volatile and a higher percentage of the total tobacco cadmium content is efficiently transferred to mainstream tobacco smoke than many other toxic metals in tobacco. Inhaled cadmium bioaccumulates in the lungs and is distributed beyond the lungs to other tissues, with a total body biological half-life of one to two decades. Chronic cadmium exposure through tobacco use elevates blood and urine cadmium concentrations. Cadmium is a carcinogen, and an inducer of proinflammatory immune responses. Elevated exposure to cadmium is associated with reduced pulmonary function, obstructive lung disease, bronchogenic carcinoma, cardiovascular diseases including myocardial infarction, peripheral arterial disease, prostate cancer, cervical cancer, pancreatic cancer, and various oral pathologies. Cadmium and zinc have a toxicologically inverse relationship. Zinc is an essential element and is reportedly antagonistic to some manifestations of cadmium toxicity. This review summarizes associations between blood, urine, and tissue cadmium concentrations with emphasis on cadmium exposure due to tobacco use and several disease states. Available data about zinc and cadmium/zinc ratios and tobacco-related diseases is summarized from studies reporting smoking status. Collectively, data suggest that blood, urine, and tissue cadmium and cadmium/zinc ratios are often significantly different between smokers and nonsmokers and they are also different in smokers for several diseases and cancers. Additional biomonitoring data such as blood or serum and urine zinc and cadmium levels and cadmium/zinc ratios in smokers may provide further insight into the development and progression of diseases of the lung, cardiovascular system, and possibly other organs.

Minimal Risk Level Derivation for Cadmium: Acute and Intermediate Duration Exposures.

The Agency for Toxic Substances and Disease Registry (ATSDR) lists cadmium as one of its priority hazardous substances. The agency conducted a comprehensive literature review of cadmium and used the information to develop a toxicological profile that identified the full range of health effects associated with exposure to cadmium. It included an assessment that identified screening levels, termed health guidance values or minimal risk levels (MRLs), below which adverse health effects are not expected. In this paper, we describe how MRLs for cadmium are derived. For the acute inhalation MRL, the traditional no observed adverse effect level or lowest observed adverse effect level (NOAEL/LOAEL) approach is used; for the oral intermediate MRL, the benchmark dose (BMD) approach is used. MRLs were developed for the most sensitive route-specific end points, other than mortality and cancer that were sufficiently supported and justified by the data. These included an acute duration (1-14 day exposure) inhalation MRL of 0.03 µg Cd/m3 for alveolar histiocytic infiltration and focal inflammation in alveolar septa and an intermediate duration (15-365 day exposure) oral MRL of 0.5 µg Cd/kg/day for decreased bone mineral density.

Polychlorinated biphenyls: New evidence from the last decade.

Millions of pounds of polychlorinated biphenyl (PCB) compounds have been produced in multiple countries for industrial applications over the last several decades. PCB exposure induces various adverse health effects in animals and humans. Environmental and occupational exposures to PCBs have been associated with liver, kidney, endocrine, and neurodevelopmental adverse effects. We have collected and reviewed animal and human data cited in the US National Library of Medicine from 2000 to 2010. In brief, our review shows new evidence, that is, in animal studies, exposure to one of the PCBs, A1221, induces a significant alteration of serum luteinizing hormone. The effects were more profound in the F2 generation, particularly with respect to fluctuations in hormones and reproductive tract tissues across the estrous cycle. Morphological analyses of brain tissue from rats exposed to A1254 confirmed the results of an earlier work which showed that the relative size of the intra- and infrapyramidal (II-P) mossy fibers was smaller than that in the controls and also reduction in growth was selective for the II-P mossy fibers. PCB exposure increased anogenital distance and prostate size but decreased epididymal weight, epididymal sperm count, and motile epididymal sperm count. No effects were observed on testicular weight or size. The epidemiological data showed an association between diabetes mellitus prevalence and elevated concentrations of PCB 153. Additionally, prenatal PCB exposure studies were associated with a smaller thymic index at birth and could adversely affect immune responses to childhood vaccinations and resistance to respiratory infections. PCB exposure was also reported to adversely affect enamel development in children in a dose-dependent manner. Because PCBs and their metabolites are potential health hazards, understanding the risk factors associated with individual PCBs, PCB mixtures, and PCB metabolites is important. PCB exposures of vulnerable populations (pregnant women, fetuses, infants, and children) are of particular concern because of heightened sensitivity during this period of brain development.

Comparison of phenotypic and virulence genes characteristics in human and chicken isolates of Proteus mirabilis.

The objective of this work is to compare the phenotypic and virulence genes characteristics in human and chicken isolates of Proteus mirabilis. The bacterial examination of 50 livers of individual broilers, marketed by four major outlets, revealed a high recovery of P. mirabilis (66%), and a low recovery frequency of Salmonella spp. (4%), Serratia odorifera (2%), Citrobacter brakii (2%), and Providencia stuartii (2%). The phenotypic biochemical characterization of the recovered 33 chicken isolates of P. mirabilis were compared to 30 human isolates (23 urinary and six respiratory isolates). The comparison revealed significant differences in the presence of gelatinase enzyme (100% presence in chicken isolates versus 91.3 and 83.3% presence in human urinary and respiratory isolates, respectively, P,0.05). The H(2)S production occurred in 100% of chicken isolates versus 95.6 and 66.7% presence in human urinary and respiratory isolates, respectively, P,0.05). The other 17 biochemical characteristics did not differ significantly among the three groups of isolates (P.0.05). Two virulence genes, the mrpA and FliL, were having a typical 100% presence in randomly selected isolates of P. mirabilis recovered from chicken livers (N510) versus isolates recovered from urinary (N55) and respiratory specimens of humans (N55) (P.0.05). The average percentage similarity of mrpA gene nucleotide sequence of poultry isolates to human urinary and respiratory isolates was 93.2 and 97.5-%, respectively. The high similarity in phenotypic characteristics, associated with typical frequency of presence of two virulence genes, and high similarity in sequences of mrpA gene among poultry versus human P. mirabilis isolates justifies future investigations targeting the evaluation of adaptable pathogenicity of avian Proteus mirabilis isolates to mammalian hosts.

The impact of toxicology on public health policy and service: an update.

The Division of Toxicology, Agency for Toxic Substances and Disease Registry (ATSDR) has a Congressional mandate to develop toxicological profiles for chemicals of greatest concern at hazardous waste sites. These chemical profiles provide a comprehensive evaluation and interpretation of the health effects, chemical and physical properties, production and use, potential for human exposure, analytical methodologies, and regulations and advisories for those chemicals. In addition, these profiles identify critical gaps in the knowledge base for these chemicals and identify levels of significant human exposure. Health assessors and other public health officials use this information to make critical decisions regarding the potential for adverse health effects at hazardous waste sites and other chemical-release events through such activities as public health assessments, chemical-specific and health-specific consultations, health-guidance-value derivations, database development, and emergency response actions. In a previous paper, we provided an overview of six specific public-health activities conducted by the ATSDR Division of Toxicology and examined how these activities have made unique impacts on public health policy and service. In this paper, we follow up on two of these, ATSDR polychlorinated biphenyls (PCBs) activities and ATSDR mercury activities, and examine their long-term, continually evolving impacts on public health policy and service.

The hypothalamo-pituitary-thyroid (HPT) axis: a target of nonpersistent ortho-substituted PCB congeners.

Coplanar polychlorinated biphenyls (PCBs) cause adverse effects in developing and adult animals. Less is known about the effects of nonplanar ortho-substituted PCBs. We investigated the effects of 2 nonplanar PCB congeners, 95 (2,3,6-2',5'-penta CB) or 101 (2,4,5-2',5'-penta CB), and estradiol on selected endocrine parameters. In Study 1, weanling female Sprague-Dawley (S-D) rats were given a single dose of PCB 95 ip at 4, 8, 16, and 32 mg/kg/day for 2 consecutive days and killed 24 h after the last dose. PCB 95 exposure caused a dose-dependent (p < 0.001) decrease in serum thyroxine (T4) levels. Serum thyroid stimulating hormone (TSH) concentrations did not change, but prolactin (PRL) levels increased in a nonlinear (with dose) manner. No significant changes were seen in thyroid gland morphology and pituitary lactotroph number. In Study 2, progression or regression of effects was assessed by lengthening the time and a second congener was tested. Weanling female S-D rats received a single dose of PCB 95 or PCB 101 ip at 16 and 32 mg/kg/day for 2 days and were killed 48 h after the last dose. PCB 95 and PCB 101 both decreased serum T4 (p < 0.001) and hypothalamic dopamine (DA; p < 0.05) levels. No changes were seen in serum triiodothyronine (T3), TSH, and PRL concentrations. Morphological analysis of the thyroid gland showed a decrease (p < 0.05) in colloid area in rats treated with PCB 95 or 101. However, the epithelial cell height increased only in PCB 95 treated rats. Thyroid epithelial cell proliferation increased (p < 0.05) following exposure to estradiol and PCB 95. The results suggest that the HPT axis appears to be a target of ortho-substituted PCBs. PCB 95 was more effective than PCB 101 in causing these changes.