Modification by hemochromatosis gene polymorphisms of the association between traffic-related air pollution and cognition in older men: a cohort study

Background: Previous studies found effect modification of associations between traffic-related air pollution and cardiovascular outcomes by polymorphisms in the hemochromatosis gene (HFE). As traffic-related air pollution may impact cognition through effects on cardiovascular health or through mechanisms which may also influence cardiovascular outcomes, we hypothesized that HFE polymorphisms would also modify a previously observed association between traffic-related air pollution exposure and cognition in older men. Methods: We considered data from 628 participants of the VA Normative Aging Study. We estimated long term exposure to black carbon (BC), a marker of traffic related air pollution, using a spatio-temporal land use regression model. We assessed cognition using the Mini-Mental State Examination (MMSE), a test of global function, and performance on a battery of other tests, covering a wide range of domains. We investigated whether variants of HFE C282Y and H63D modified the association between BC and having a low MMSE score using logistic models with generalized estimating equations and multiplicative interaction terms. Similarly, we assessed whether HFE variants modified the association between BC and performance on the cognitive battery using linear mixed models with multiplicative interaction terms. Results: Our results suggest modification of the BC-cognition association by HFE C282Y, although the test of interaction did not achieve statistical significance. In multivariable-adjusted models, participants who lacked a HFE C282Y variant (CC) exhibited an adverse association between BC and total cognition z-score (beta for a doubling in BC concentration: -0.061, 95% CI: -0.115, -0.007), while we did not observe an association in participants with at least one variant genotype (CY or YY) (beta for a doubling in BC concentration: 0.073, 95% CI: -0.081, 0.228; p-value for interaction: 0.11). The pattern of association was similar for analyses considering performance on the Mini-Mental State Examination. There was little evidence to support effect modification of the BC-cognition association by the HFE H63D genotype. Conclusions: Our data suggest that older adults who lack an HFE C282Y variant may be more susceptible to an adverse effect of traffic-related air pollution exposure on cognition. This finding and the proposed biological mechanism require confirmation

Mitochondrial haplogroups modify the effect of black carbon on age-related cognitive impairment

Background: Traffic-related air pollution has been linked with impaired cognition in older adults, possibly due to effects of oxidative stress on the brain. Mitochondria are the main source of cellular oxidation. Haplogroups in mitochondrial DNA (mtDNA) mark individual differences in oxidative potential and are possible determinants of neurodegeneration. The aim of this study was to investigate whether mtDNA haplogroups determined differential susceptibility to cognitive effects of long-term exposure to black carbon (BC), a marker of traffic-related air pollution. Methods: We investigated 582 older men (72 ± 7 years) in the VA Normative Aging Study cohort with ≤4 visits per participant (1.8 in average) between 1995–2007. Low (≤25) Mini Mental State Examination (MMSE) was used to assess impaired cognition in multiple domains. We fitted repeated-measure logistic regression using validated-LUR BC estimated in the year before their first visit at the participant’s address. Results: Mitochondrial haplotyping identified nine haplogroups phylogenetically categorized in four clusters. BC showed larger effect on MMSE in Cluster 4 carriers, including I, W and X haplogroups, [OR = 2.7; 95% CI (1.3-5.6)], moderate effect in Cluster 1, including J and T haplogroups [OR = 1.6; 95% CI: (0.9-2.9)], and no effect in Cluster 2 (H and V haplogroups) [OR = 1.1; 95% CI: (0.8-1.5)] or Cluster 3 (K and U haplogroups) [OR = 1.0; 95% CI: (0.6-1.6)]. BC effect varied only moderately across the I, X, and W haplogroups or across the J and T haplogroups. Conclusions: The association of BC with impaired cognition was worsened in carriers of phylogenetically-related mtDNA haplogroups in Cluster 4. No BC effects were detected in Cluster 2 and 3 carriers. MtDNA haplotypes may modify individual susceptibility to the particle cognitive effects

Development of a Health-Protective Drinking Water Level for Perchlorate

We evaluated animal and human toxicity data for perchlorate and identified reduction of thyroidal iodide uptake as the critical end point in the development of a health-protective drinking water level [also known as the public health goal (PHG)] for the chemical. This work was performed under the drinking water program of the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. For dose–response characterization, we applied benchmark-dose modeling to human data and determined a point of departure (the 95% lower confidence limit for 5% inhibition of iodide uptake) of 0.0037 mg/kg/day. A PHG of 6 ppb was calculated by using an uncertainty factor of 10, a relative source contribution of 60%, and exposure assumptions specific to pregnant women. The California Department of Health Services will use the PHG, together with other considerations such as economic impact and engineering feasibility, to develop a California maximum contaminant level for perchlorate. We consider the PHG to be adequately protective of sensitive subpopulations, including pregnant women, their fetuses, infants, and people with hypothyroidism

Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Background 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. Objectives 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. Discussion 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. Conclusions 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

Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts

<p>Abstract</p> <p>Background</p> <p>Bronchial fibroblasts contribute to airway remodelling, including airway wall fibrosis. Transforming growth factor (TGF)-β1 plays a major role in this process. We previously revealed the importance of the mevalonate cascade in the fibrotic response of human airway smooth muscle cells. We now investigate mevalonate cascade-associated signaling in TGFβ1-induced fibronectin expression by bronchial fibroblasts from non-asthmatic and asthmatic subjects.</p> <p>Methods</p> <p>We used simvastatin (1-15 μM) to inhibit 3-hydroxy-3-methlyglutaryl-coenzyme A (HMG-CoA) reductase which converts HMG-CoA to mevalonate. Selective inhibitors of geranylgeranyl transferase-1 (GGT1; GGTI-286, 10 μM) and farnesyl transferase (FT; FTI-277, 10 μM) were used to determine whether GGT1 and FT contribute to TGFβ1-induced fibronectin expression. In addition, we studied the effects of co-incubation with simvastatin and mevalonate (1 mM), geranylgeranylpyrophosphate (30 μM) or farnesylpyrophosphate (30 μM).</p> <p>Results</p> <p>Immunoblotting revealed concentration-dependent simvastatin inhibition of TGFβ1 (2.5 ng/ml, 48 h)-induced fibronectin. This was prevented by exogenous mevalonate, or isoprenoids (geranylgeranylpyrophosphate or farnesylpyrophosphate). The effects of simvastatin were mimicked by GGTI-286, but not FTI-277, suggesting fundamental involvement of GGT1 in TGFβ1-induced signaling. Asthmatic fibroblasts exhibited greater TGFβ1-induced fibronectin expression compared to non-asthmatic cells; this enhanced response was effectively reduced by simvastatin.</p> <p>Conclusions</p> <p>We conclude that TGFβ1-induced fibronectin expression in airway fibroblasts relies on activity of GGT1 and availability of isoprenoids. Our results suggest that targeting regulators of isoprenoid-dependent signaling holds promise for treating airway wall fibrosis.</p

Non-hispanic whites have higher risk for pulmonary impairment from pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Disparities in outcomes associated with race and ethnicity are well documented for many diseases and patient populations. Tuberculosis (TB) disproportionately affects economically disadvantaged, racial and ethnic minority populations. Pulmonary impairment after tuberculosis (PIAT) contributes heavily to the societal burden of TB. Individual impacts associated with PIAT may vary by race/ethnicity or socioeconomic status.</p> <p>Methods</p> <p>We analyzed the pulmonary function of 320 prospectively identified patients with pulmonary tuberculosis who had completed at least 20 weeks standard anti-TB regimes by directly observed therapy. We compared frequency and severity of spirometry-defined PIAT in groups stratified by demographics, pulmonary risk factors, and race/ethnicity, and examined clinical correlates to pulmonary function deficits.</p> <p>Results</p> <p>Pulmonary impairment after tuberculosis was identified in 71% of non-Hispanic Whites, 58% of non-Hispanic Blacks, 49% of Asians and 32% of Hispanics (<it>p </it>< 0.001). Predictors for PIAT varied between race/ethnicity. PIAT was evenly distributed across all levels of socioeconomic status suggesting that PIAT and socioeconomic status are not related. PIAT and its severity were significantly associated with abnormal chest x-ray, <it>p </it>< 0.0001. There was no association between race/ethnicity and time to beginning TB treatment, <it>p </it>= 0.978.</p> <p>Conclusions</p> <p>Despite controlling for cigarette smoking, socioeconomic status and time to beginning TB treatment, non-Hispanic White race/ethnicity remained an independent predictor for disproportionately frequent and severe pulmonary impairment after tuberculosis relative to other race/ethnic groups. Since race/ethnicity was self reported and that race is not a biological construct: these findings must be interpreted with caution. However, because race/ethnicity is a proxy for several other unmeasured host, pathogen or environment factors that may contribute to disparate health outcomes, these results are meant to suggest hypotheses for further research.</p