There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice 1,2 , underlies the variability in airway responsiveness to inhaled LPS in humans 3 . Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene-sequence changes can alter the ability of the host to respond to environmental stress. We investigated the genetic basis for the physiologic response to inhaled endotoxin or LPS for several reasons. First, endotoxin is associated with the development and progression of asthma and other forms of airway disease. In the domestic setting, the concentration of endotoxin is associated with the clinical severity of asthma 4 , and, among exposed workers, endotoxin is the most significant component of the bioaerosol that is associated with the development 5 and progression 6 of airway disease. Endotoxin may also have a role in the pathophysiological consequences of air pollution 7 . Second, the ability of the host to respond to endotoxin is highly variable. Differences between individuals have been reported in the release and synthesis of cytokines by human monocytes stimulated with LPS in vitro 8 , and a patient with recurrent bacterial infections has been reported to be refractory to the in vivo and in vitro effects of LPS (ref. 9). We have recently found that normal, healthy, non-asthmatic subjects demonstrate a reproducible airway response to an incremental LPS inhalation challenge test; some subjects developed airflow obstruction when challenged with low concentrations of LPS and others were unaffected by high concentrations of inhaled LPS (ref. 3). Third, the

https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.files/fileID/13755

TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.

Zinc and immune function: the biological basis of altered resistance to infection.

Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.

https://www.mdpi.com/1660-4601/7/4/1342/pdf

The Essential Toxin: Impact of Zinc on Human Health

Exposures to bioaerosols in the occupational environment are associated with a wide range of health effects with major public health impact, including infectious diseases, acute toxic effects, allergies and cancer. Respiratory symptoms and lung function impairment are the most widely studied and probably among the most important bioaerosol-associated health effects. In addition to these adverse health effects some protective effects of microbial exposure on atopy and atopic conditions has also been suggested. New industrial activities have emerged in recent years in which exposures to bioaerosols can be abundant, e.g. the waste recycling and composting industry, biotechnology industries producing highly purified enzymes and the detergent and food industries that make use of these enzymes. Dose-response relationships have not been established for most biological agents and knowledge about threshold values is sparse. Exposure limits are available for some contaminants, e.g. wood dust, subtilisins (bacterial enzymes) and flour dust. Exposure limits for bacterial endotoxin have been proposed. Risk assessment is seriously hampered by the lack of valid quantitative exposure assessment methods. Traditional culture methods to quantify microbial exposures have proven to be of limited use. Non-culture methods and assessment methods for microbial constituents [e.g. allergens, endotoxin, beta(1-->3)-glucans, fungal extracellular polysaccharides] appear more successful; however, experience with these methods is generally limited. Therefore, more research is needed to establish better exposure assessment tools and validate newly developed methods. Other important areas that require further research include: potential protective effects of microbial exposures on atopy and atopic diseases, inter-individual susceptibility for biological exposures, interactions of bioaerosols with non-biological agents and other potential health effects such as skin and neurological conditions and birth effects.

/pdf/bioaerosol-health-effects-and-exposure-assessment-progress-31appz2yq3.pdf

Bioaerosol Health Effects and Exposure Assessment: Progress and Prospects

To assess whether school environments can adversely affect academic performance, we review scientific evidence relating indoor pollutants and thermal conditions, in schools or other indoor environments, to human performance or attendance. We critically review evidence for direct associations between these aspects of indoor environmental quality (IEQ) and performance or attendance. Secondarily, we summarize, without critique, evidence on indirect connections potentially linking IEQ to performance or attendance. Regarding direct associations, little strongly designed research was available. Persuasive evidence links higher indoor concentrations of nitrogen dioxide to reduced school attendance, and suggestive evidence links low ventilation rates to reduced performance. Regarding indirect associations, many studies link indoor dampness and microbiologic pollutants (primarily in homes) to asthma exacerbations and respiratory infections, which in turn have been related to reduced performance and attendance. Also, much evidence links poor IEQ (e.g., low ventilation rate, excess moisture, or formaldehyde) with adverse health effects in children and adults and documents dampness problems and inadequate ventilation as common in schools. Overall, evidence suggests that poor IEQ in schools is common and adversely influences the performance and attendance of students, primarily through health effects from indoor pollutants. Evidence is available to justify (1) immediate actions to assess and improve IEQ in schools and (2) focused research to guide IEQ improvements in schools.

/pdf/do-indoor-pollutants-and-thermal-conditions-in-schools-1hk3qn9kvq.pdf

Do indoor pollutants and thermal conditions in schools influence student performance? A critical review of the literature

In sensitized subjects, exposure to the mite allergen appears to be only one of several factors leading to asthma. We hypothesized that in association with allergen exposure, endotoxin, a proinflammatory agent present in house dust (HD), influences the severity of asthma. Using a cross-sectional study design, we investigated a group of 69 consecutive dust mite (HDM)-sensitized subjects defined as having rhinitis (n = 20) or asthma (n = 49); the latter were evaluated functionally and clinically by three different scores and by their need for daily medication. Concentrations of Dermatophagoides pteronyssinus p I allergen (Der p I) (by two-site monoclonal antibody enzyme-linked immunosorbent assay [ELISA]), guanine (by high-pressure liquid chromatography [HPLC]), and endotoxin (by modified Limulus. amebocyte lysate assay) were measured in HD collected in duplicate from the mattresses and floors in each subject's home. The concentrations of Der p I and of guanine in HD collected from mattresses were significantly higher in asthmatic subjects than in those with rhinitis (p or = 10 micrograms/g HD and/or guanine > or = 0.10 mg/100 mg HD), the severity of asthma was unrelated to mite allergen concentration in HD. On the contrary, the severity of asthma was related to concomitant exposure to endotoxin in HD, since the concentration of HD endotoxin was significantly and inversely correlated with FEV1 (p < 0.05), FEV1/FVC (p < 0.02), daily need for oral (p < 0.01) and inhaled (p < 0.01) corticosteroids, daily need for beta 2 agonists (p < 0.001) and xanthines (p < 0.01), and clinical scores such as the modified Aas score (p < 0.01). In HDM-sensitized subjects exposed to a high level of allergen, the concentration of endotoxin measured in HD is an important determinant of asthma severity.

Severity of asthma is related to endotoxin in house dust

Beneficial effects of oral zinc supplementation on the immune response of old people

Anti-IgM stimulation of B cells is decreased in the presence of maternal serum as compared to control media. This inhibiting influence of maternal serum is observed during the priming of the B cells. The progression of B cells into cellular proliferation was not influenced by maternal serum. At the level of the immunoglobulin secretion, the influence of maternal serum was also shown. A significant down regulation of the IgM, no change of the IgG production, and an enhanced secretion of IgA and IgE was demonstrated in the presence of maternal serum as compared to control media. It has been suggested that the maternal IgG fraction contains a molecule partly responsible for these changes. Furthermore, the CD23 antigen is increased when B cells are stimulated in the presence of a pool of maternal IgG. All the findings concerning maternal IgG were more pronounced when retroplacental IgG was used instead of peripheral maternal IgG. This observation suggests that the factor responsible for the B cell changes is ...

Modulation of B cell stimulation by maternal serum

Increased DNA synthesis and immunoglobulin secretion was observed in human peripheral blood lymphocytes (PBL) cultured in vitro with soluble protein A from Staphylococcus aureus (Sp-A). Optimal Ig secretion was obtained in 6 day cultures containing 1 x 10(6) cells/ml and 10 microgram/ml Sp-A. The presence of 5 x 10(-5) M 2-mercaptoethanol in the culture medium as well as careful selection of foetal calf serum were needed for optimal results. In response to Sp-A stimulation, the three main classes of immunoglobulins were secreted by PBL. In some individuals, concentration of Sp-A optimal for IgG and IgM secretion inhibited IgA production. Immunoglobulin-containing cells were less abundant (0.5--5% of total cells) and smaller in Sp-A than in PWM-stimulated cultures (5--15%). The data suggest that Sp-A and PWM stimulated different subsets of circulating lymphocytes.

In vitro response of human peripheral blood lymphocytes of protein A. DNA synthesis and generation of cells synthesizing the three major classes of Ig.

Differential regulation of antibody responses to native VS digested Betalactoglobulin in cow's milk fed mice

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