[Show abstract][Hide abstract] ABSTRACT: Abstract Diisocyanates are the most common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants in inflammatory response genes (TNFα, IL1α, IL1β, IL1RN, IL10, TGFB1, ADAM33, ALOX-5, PTGS1, PTGS2 and NAG-1/GDF15) are associated with increased susceptibility to diisocyanate asthma (DA). These genes were selected based on their role in asthmatic inflammatory processes and previously reported associations with asthma phenotypes. The main study population consisted of 237 Caucasian French Canadians from among a larger sample of 280 diisocyanate-exposed workers in two groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95) and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5' nuclease PCR assay. After adjusting for potentially confounding variables of age, smoking status and duration of exposure, the PTGS1 rs5788 and TGFB1 rs1800469 single nucleotide polymorphisms (SNP) showed a protective effect under a dominant model (OR = 0.38; 95% CI = 0.17, 0.89 and OR = 0.38; 95% CI = 0.18, 0.74, respectively) while the TNFα rs1800629 SNP was associated with an increased risk of DA (OR = 2.08; 95% CI = 1.03, 4.17). Additionally, the PTGS2 rs20417 variant showed an association with increased risk of DA in a recessive genetic model (OR = 6.40; 95% CI = 1.06, 38.75). These results suggest that genetic variations in TNFα, TGFB1, PTGS1 and PTGS2 genes contribute to DA susceptibility.
Journal of Immunotoxicology 02/2015; DOI:10.3109/1547691X.2015.1017061 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between single nucleotide polymorphisms (SNPs) located across the major histocompatibility complex and susceptibility to diisocyanate-induced asthma (DA).
The study population consisted of 140 diisocyanate-exposed workers. Genotyping was performed using the Illumina GoldenGate major histocompatibility complex panels.
The HLA-E rs1573294 and HLA-DPB1 rs928976 SNPs were associated with an increased risk of DA under dominant (odds ratio [OR], 6.27; 95% confidence interval [CI], 2.37 to 16.6; OR, 2.79, 95% CI, 0.99 to 7.81, respectively) and recessive genetic models (OR, 6.27, 95% CI, 1.63 to 24.13; OR, 10.10, 95% CI, 3.16 to 32.33, respectively). The HLA-B rs1811197, HLA-DOA rs3128935, and HLA-DQA2 rs7773955 SNPs conferred an increased risk of DA in a dominant model (OR, 7.64, 95% CI, 2.25 to 26.00; OR, 19.69, 95% CI, 2.89 to 135.25; OR, 8.43, 95% CI, 3.03 to 23.48, respectively).
These results suggest that genetic variations within HLA genes play a role in DA risk.
Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 04/2014; 56(4):382-7. DOI:10.1097/JOM.0000000000000138 · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Supported by several epidemiological studies and a large number of animal studies, certain polyfluorinated alkyl acids (PFAAs) are believed to be immunotoxic, affecting particularly humoral immunity. Our aim was to investigate the relationship between the antibody response following vaccination with an inactivated trivalent influenza vaccine and circulating levels of perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). The study population consisted of 411 adults living in the mid-Ohio region of Ohio and West Virginia where public drinking water had been inadvertently contaminated with PFOA. They participated in a larger cross-sectional study in 2005/6, and were followed up in 2010, by which time serum levels of PFOA had been substantially reduced but were still well above those found in the general population. Hemagglutination inhibition (HI) tests were conducted on serum samples collected pre-influenza vaccination and 21+/- 3 days post-vaccination in 2010. Serum samples were also analyzed for PFOA and PFOS concentrations (median, 31.5 and 9.2 ng/ml respectively). Questionnaires were conducted regarding the occurrence and frequency of recent (during the last 12 months) respiratory infections. Our findings indicated that elevated PFOA serum concentrations are associated with reduced antibody titer rise, particularly to A/H3N2 influenza virus, and an increased risk of not attaining the antibody threshold considered to offer long term protection. Whilst the direct relationship between weakened antibody response and clinical risk of influenza is not clear, we did not find evidence for an association between self-reported colds or influenza and PFOA levels nor between PFOS serum concentrations and any of the endpoints examined.
[Show abstract][Hide abstract] ABSTRACT: Abstract An historical perspective of immunotoxicology is presented beginning from early observations in which exposure to workplace environments led to unexpected immune-mediated lung diseases to its eventual evolution as a sub-discipline in toxicology. As with most toxicology disciplines, immunotoxicology originated from concerns by scientists within industry and government as well as medical professionals to limit human exposure to agents that can potentially effect human health. The basis for these concerns originated from laboratory studies in experimental models and clinical observations that suggested certain industrial and agrochemicals, pharmaceuticals and consumer products were capable of inadvertently interacting with the immune system and cause adverse health effects. The types of immunopathologies observed and mechanisms responsible were found to be broad, being dependent upon the physiochemical properties of an agent, exposure route, and target organ/tissue, and included allergic/hypersensitivity responses, immune dysfunction, manifested by suppression or, in rare instances, stimulation, autoimmune or autoimmune-like diseases, and chronic inflammatory disorders.
Journal of Immunotoxicology 10/2013; 11(3). DOI:10.3109/1547691X.2013.837121 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influence of genetic variability within the major histocompatibility complex (MHC) region on variations in immune responses to childhood vaccination was investigated. The study group consisted of 135 healthy infants who had been immunized with hepatitis B (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using Illumina Goldengate MHC panels (Mapping and Exon Centric). At the 1 year post vaccination check-up total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. A number of single nucleotide polymorphisms (SNPs) within MHC Class I and II genes were found to be associated with variations in the vaccine specific antibody responses and serum levels of immunoglobulins (IgG, IgM) and IgG isotypes (IgG1, IgG4) (all at p<0.001). Linkage disequilibrium patterns and functional annotations showed that significant SNPs were strongly correlated with other functional regulatory SNPs. These SNPs were found to regulate the expression of a group of genes involved in antigen processing and presentation including HLA-A, HLA-C, HLA-G, HLA-H, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DOB, and TAP-2. The results suggest that genetic variations within particular MHC genes can influence immune response to common childhood vaccinations, which in turn may influence vaccine efficacy.
[Show abstract][Hide abstract] ABSTRACT: Irritant hand dermatitis (IHD) is common in health care workers.
We studied endogenous irritant contact dermatitis threshold by patch testing and exogenous factors such as season and hand washing for their association with IHD in health care workers.
Irritant patch testing with sodium lauryl sulfate (SLS), sodium hydroxide, and benzalkonium chloride at varying concentrations was measured in 113 health care workers. Examination for hand dermatitis occurred at 1-month intervals for a period of 6 months in the Midwestern United States.
Positive patch testing to low-concentration SLS was associated with IHD (P = 0.0310) after adjusting for age, sex, ethnicity, season, history of childhood flexural dermatitis, mean indoor relative humidity, and glove and hand sanitizer usage. Subjects with a positive patch test to SLS were 78% more likely to have occurrence of IHD (incidence rate ratio [IRR] = 1.78; 95% confidence interval [CI], 0.92-3.45). Hand washing frequency (≥10 times a day; IRR = 1.55; 95% CI, 1.01-2.39) and cold season (IRR = 2.76; 95% CI, 1.35-5.65) were associated with IHD. No association was found between history of childhood flexural dermatitis and IHD in this population.
Both genetic and environmental factors are important in the etiology of IHD and should be considered in designing strategies to protect, educate, and treat susceptible individuals.
[Show abstract][Hide abstract] ABSTRACT: Background:
Several epidemiological cross-sectional studies have found positive associations between serum concentrations of lipids and perfluorooctanoic acid (PFOA, or C8). A longitudinal study should be less susceptible to biases from uncontrolled confounding or reverse causality.
We investigated the association between within-individual changes in serum PFOA and perfluorooctanesulfonic acid (PFOS) and changes in serum lipid levels (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) over a 4.4-year period. The study population consisted of 560 adults living in parts of Ohio and West Virginia where public drinking water had been contaminated with PFOA. They had participated in a cross-sectional study in 2005-2006, and were followed up in 2010, by which time exposure to PFOA had been substantially reduced.
Overall serum concentrations of PFOA and PFOS fell by half from initial geometric means of 74.8 and 18.5 ng/mL, respectively, with little corresponding change in LDL cholesterol (mean increase 1.8%, standard deviation 26.6%). However, there was a tendency for people with greater declines in serum PFOA or PFOS to have greater LDL decrease. For a person whose serum PFOA fell by half, the predicted fall in LDL cholesterol was 3.6% (95% confidence interval = 1.5-5.7%). The association with a decline in PFOS was even stronger, with a 5% decrease in LDL (2.5-7.4%).
Our findings from this longitudinal study support previous evidence from cross-sectional studies of positive associations between PFOA and PFOS in serum and LDL cholesterol.
[Show abstract][Hide abstract] ABSTRACT: Perfluorooctanoic acid (PFOA, 'C8') and perfluoroctane sulphonate (PFOS) are environmentally stable compounds with industrial and consumer uses and long half-lives in humans. Concern has been raised over chronic exposure effects to human health, especially in relation to cholesterol metabolism. Here, we explore the association between exposure to PFOA and PFOS and the in vivo expression of genes involved in cholesterol metabolism. We studied 290 individuals exposed to background levels of PFOS and elevated concentrations of PFOA through drinking water. Using adjusted linear regression models, we found inverse associations between serum PFOA levels and the whole blood expression level of genes involved in cholesterol transport (NR1H2, NPC1 and ABCG1; p=0.002, 0.026 and 0.014 respectively). A positive association was seen between PFOS and a transcript involved in cholesterol mobilisation (NCEH1; p=0.018), and a negative relationship with a transcript involved in cholesterol transport (NR1H3; p=0.044). When sexes were analysed separately, reductions in the levels of mRNAs involved in cholesterol transport were seen with PFOA in men (NPC1, ABCG1, and PPARA; p=0.025, 0.024 and 0.012 respectively) and in women (NR1H2 expression; p=0.019), whereas an increase in the levels of a cholesterol mobilisation transcript (NCEH1; p=0.036) was noted in women alone. PFOS was positively associated with expression of genes involved in both cholesterol mobilisation and transport in women (NCEH1 and PPARA; p=0.003 and 0.039 respectively), but no effects were evident in men. This is the first report of associations between the in vivo expression of genes involved in cholesterol metabolism and exposure to PFOA or PFOS, suggested that exposure to these compounds may promote a hypercholesterolaemic environment, with wider implications for human disease.
Environment international 04/2013; 57-58C:2-10. DOI:10.1016/j.envint.2013.03.008 · 5.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quinacrine has been widely used in treatment of parasitic diseases such as malaria and giardiasis, and in the treatment of autoimmune diseases. Quinacrine has also been used as an effective substitute for surgical contraception by causing occlusion of the fallopian tube. This minimally invasive treatment protocol involves intrauterine insertion of the drug in the form of pellets and has been studied in humans in a number of countries, including the United States. Despite its development in the 1970s, the cellular and molecular events induced by quinacrine in the human fallopian tube have not been described. Here we describe a plausible mechanism for quinacrine action in the fallopian tube. This is manifested as an acute pro-inflammatory response in the uterus and fallopian tube, characterized by loss of epithelial cell adhesion. This response relies on properties of gated channels found on the surface of epithelial cells in the reproductive tract. While the uterus returns to normal, the inflammatory response affects the uterotubal junction and transmural segment of the human fallopian tube, and initiates formation of mature collagen in the lumen of the fallopian tube, resulting in its permanent occlusion. The response within the fallopian tube appears similar to the protective mechanisms that have evolved in women to minimize the likelihood of systemic infection from Neisseria gonorrhoeae, and to some extent from Chlamydia trachomatis. This review could assist in development of experimental models used in investigating the mechanisms of fibrotic responses in humans as well as development of techniques for permanent non-surgical female contraception.
[Show abstract][Hide abstract] ABSTRACT: Recently, a genome wide association study (GWAS) conducted in Korean subjects identified three CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, and rs4378283) associated with diisocyanate induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5' nuclease PCR assay collected from 410 diisocyanate exposed and predominantly Canadian workers including: 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA-); and 147 HDI-exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs were significantly associated with DA+ when compared to AWs but not in comparison to DA- workers (p≤ 0.05). After adjusting for potentially confounding variables of age, smoking status and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs [OR= 9.05 (95% CI:1.69, 48.54) and OR = 6.82 (95% CI:1.65, 28.24), respectively]. In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of cadherins in the disease process.
[Show abstract][Hide abstract] ABSTRACT: Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95); symptomatic diisocyanate workers with a negative SIC (DA(-), n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5'-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA(+) and DA(-) groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA(+) and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.
[Show abstract][Hide abstract] ABSTRACT: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the pathogenesis of osteoarthritis (OA). However, the link between these compounds and OA remains unknown. In this study, the authors investigated the association of OA with PFOA and PFOS in a population of 49,432 adults from 6 PFOA-contaminated water districts in the mid-Ohio Valley (2005-2006). Participants completed a comprehensive health survey; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history, including physician diagnosis of osteoarthritis, was assessed via self-report. Analyses included adjustment for demographic and lifestyle characteristics, body mass index, and other potential confounders. Reported OA showed a significant positive association with PFOA serum levels (for highest quartile of PFOA vs. lowest, adjusted odds ratio = 1.3, 95% confidence interval: 1.2, 1.5; P-trend = 0.00001) and a significant inverse association with PFOS (for highest quartile vs. lowest, adjusted odds ratio = 0.8, 95% confidence interval: 0.7, 0.9; P-trend = 0.00005). The relation between PFOA and OA was significantly stronger in younger and nonobese adults. Although the cross-sectional nature of this large, population-based study limits causal inference, the observed strong, divergent associations of reported OA with PFOA and PFOS may have important public health and etiologic implications and warrant further investigation.
American journal of epidemiology 06/2011; 174(4):440-50. DOI:10.1093/aje/kwr107 · 5.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This companion article offers an alternative interpretation for the quinacrine-induced uterine tumors observed in a 2-year bioassay in rats (CaBio, Cancel et al., 2010), and provides additional data from two new experiments that support a different interpretation and analysis. Our major premise is that the design of the Cancel et al. bioassay was flawed, particularly regarding dose selection that allowed for misinterpretation of carcinogenic activity. We feel the totality of the information provided herein dictates that the doses (70/70, 70/250 and 70/350 mg/kg quinacrine) causing uterine tumors in their study clearly exceeded the maximum tolerated dose (MTD) typically administered in chronic cancer studies. Our new data support this conclusion and serve to explain the development of lesions, especially the uterine tumors, they have reported. We argue that the rat uterus is not a valid surrogate for the human fallopian tube. Further, we maintain that quinacrine is not genotoxic in vivo, as suggested in their paper. In summary, we believe that quinacrine is not carcinogenic in rats at doses that do not exceed the MTD.
[Show abstract][Hide abstract] ABSTRACT: The magnitude of the immune response to vaccinations can be influenced by genetic variability. In the present study, we aimed to investigate whether cytokine or cytokine receptor gene polymorphisms were associated with variations in the immune response to childhood vaccination. The study group consisted of 141 healthy infants who had been immunized with hepatitis B vaccine (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using a 5' nuclease PCR assay. Post vaccination total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. Significant associations were observed between SNPs in the TNFalpha, IL-12B, IL-4Ralpha, and IL-10 genes and vaccine-specific immune responses (p<0.05). In addition, SNPs in the IL-1beta, TNFalpha, IL-2, IL-4, IL-10, IL-4Ralpha, and IL-12B genes were associated with variations in serum levels of immunoglobulins (IgG, IgA, IgM) and IgG isotypes (IgG1-IgG3) (p<0.05). These data suggest that genetic variations in cytokine genes can influence vaccine-induced immune responses in infants, which in turn may influence vaccine efficacy.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate whether the expression of specific genes in peripheral blood can be used as surrogate marker(s) to detect and distinguish target organ toxicity induced by chemicals in rats. Rats were intraperitoneally administered a single, acute dose of a well-established hepatotoxic (acetaminophen) or a neurotoxic (methyl parathion) chemical. Administration of acetaminophen (AP) in the rats resulted in hepatotoxicity as evidenced from elevated blood transaminase activities. Similarly, administration of methyl parathion (MP) resulted in neurotoxicity in the rats as evidenced from the inhibition of acetyl cholinesterase activity in their blood. Administration of either chemical also resulted in mild hematotoxicity in the rats. Microarray analysis of the global gene expression profile of rat blood identified distinct gene expression markers capable of detecting and distinguishing hepatotoxicity and neurotoxicity induced by AP and MP, respectively. Differential expressions of the marker genes for hepatotoxicity and neurotoxicity were detectable in the blood earlier than the appearance of the commonly used clinical markers (serum transaminases and acetyl cholinesterase). The ability of the marker genes to detect hepatotoxicity and neurotoxicity was further confirmed using the blood samples of rats administered additional hepatotoxic (thioacetamide, dimethylnitrobenzene, and carbon tetrachloride) or neurotoxic (ethyl parathion and malathion) chemicals. In summary, our results demonstrated that blood gene expression markers can detect and distinguish target organ toxicity non-invasively.
[Show abstract][Hide abstract] ABSTRACT: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment.
Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available.
Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects.
For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.
Environmental Health Perspectives 12/2008; 116(11):1568-75. DOI:10.1289/ehp.11516 · 7.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are environmentally widespread and persistent chemicals with multiple toxicities reported in experimental animals and humans. These compounds can trigger biological activity by activating the alpha isotype of peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that regulate gene expression; however, some biological effects may occur independently of the receptor. Activation of the peroxisome proliferator-activated receptor alpha (PPARalpha) modulates lipid and glucose homeostasis, cell proliferation and differentiation, and inflammation. Reported immunomodulation in experimental animals exposed to PFOA and PFOS has included altered inflammatory responses, production of cytokines and other proteins, reduced lymphoid organ weights, and altered antibody synthesis. Mounting experimental animal evidence suggests PPARalpha independence of some immune effects. This evidence originates primarily from studies with PPARalpha knockout models exposed to PFOA that demonstrate hepatic peroxisome proliferation, reduced lymphoid organ weights, and altered antibody synthesis. As human PPARalpha expression is significantly less than that of rodents, potential PPARalpha independence indicates that future research must explore mechanisms of action of these compounds, including PPARalpha-dependent and -independent pathways. This multiauthored review contains brief descriptions of current and recently published work exploring immunomodulation by PFOA and PFOS, as well as a short overview of other PPARalpha ligands of therapeutic and environmental interest.