Background: In air pollution time-series studies, the temporal pattern of the association of fine particulate matter (PM_2.5) and health endpoints has been observed to vary by disease category. The lag pattern of PM_2.5 chemical constituents has not been well investigated, largely because daily data have not been available.

Objectives: Using daily PM_2.5 chemical constituent data for five years in the Denver Aerosol Sources and Health (DASH) study, we explored the lag structure for hospital admissions.

Methods: PM_2.5 constituents, including elemental and organic carbon, sulfate, and nitrate, were measured daily at a central residential site from 2003 through 2007 and linked to daily hospital admission counts in the five-county Denver metropolitan area. Total hospital admissions and subcategories of respiratory and cardiovascular admissions were examined. We assessed the lag structure of relative risks of hospital admissions for PM_2.5 and four constituents on the same day and one to fourteen previous days from a constrained distributed lag model, adjusting for temperature, humidity, longer term temporal trends, and day of week using a generalized additive model.

Results: Relative risks were generally larger at shorter lags for total cardiovascular admissions but at longer lags for total respiratory admissions. The delayed lag pattern was particularly prominent for asthma. Elemental and organic carbon generally showed more immediate patterns, while sulfate and nitrate showed delayed patterns.

Conclusion: In general, PM_2.5 chemical constituents were found to have more immediate estimated effects on cardiovascular diseases and more delayed estimated effects on respiratory diseases, depending somewhat on the constituent.

Background. Obesity is a growing worldwide problem with genetic and environmental causes and an underlying basis for many diseases. Studies have shown that the toxicant-activated aryl hydrocarbon receptor (AHR) may disrupt fat metabolism and contribute to obesity. The AHR is a nuclear receptor/transcription factor that is best known for responding to environmental toxicant exposures to induce a battery of xenobiotic metabolizing genes.

Objectives. The intent of the work reported here was to test more directly the role of the AHR in obesity and fat metabolism in lieu of exogenous toxicants.

Methods. We used two congenic mouse models that differ at the Ahr gene and which encode AHRs with a 10-fold difference in signaling activity.

Results. The two Ahr mouse strains were fed a Western diet, which differentially affected body size, body fat:body mass ratios, liver size and liver metabolism, and liver mRNA and miRNA profiles. A low-fat regular diet had no significant differential effects.

Conclusions. The results suggest that the AHR plays a large and broad role in obesity and associated complications, and importantly, may provide a simple and effective therapeutic strategy to combat obesity, heart disease, and other obesity-associated illnesses.

Background: The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined.

Objectives: We and others have shown DDT activates cell signaling cascades, culminating in the activation of estrogen receptor-dependent and independent gene expression. Here, we identify a mechanism by which DDT alters cellular signaling and gene expression, independent of the estrogen receptor.

Methods: We performed a qPCR array analysis of gene expression in MCF-7 breast cancer cells using either estradiol or o,p’-DDT to identify distinct cellular gene expression responses. To elucidate the mechanisms by which DDT regulates cell signaling, molecular and pharmacological techniques were utilized.

Results: Estradiol and DDT treatment both altered the expression of many of the genes assayed, but upregulation of vascular endothelial growth factor A (VEGF-A) was observed following DDT treatment only and this increase was not affected by the pure ERα antagonist ICI. Furthermore, DDT increased the activation of the HIF-1 response element (HRE), a known enhancer of the VEGF-A gene. This DDT-mediated increase in HRE activity was augmented by the coactivator CBP and was dependent on the p38 pathway.

Conclusions: DDT upregulated the expression of several genes in MCF-7 breast cancer cells that were not altered by treatment with estradiol, including VEGF-A. We propose that this DDT-initiated, ER-independent stimulation of gene expression is due to DDT’s ability to initiate a crosstalk between MAPK signaling pathways and transcriptional coactivators.

Background: Placental tissue may furnish information on the exposure of both mother and fetus. Mercury, cadmium and lead are toxicants of interest in pregnancy, associated with alterations in child development.

Objectives: To summarize the available information regarding total mercury, cadmium and lead levels in human placenta and possible related factors.

Methods: Systematic search of PubMed, Medline, EMBASE, Lilacs, OSH and Web of Science for original papers on total mercury, cadmium or lead levels in human placenta, published in English or Spanish (1976-2011). Data on study design, population characteristics, collection and analysis of placenta specimens and main results were extracted using a standardized form.

Results: A total of 79 papers (73 different studies) were found. Mercury, cadmium and lead levels were reported in 24, 46 and 46 studies, respectively. Most studies included small convenience samples of healthy pregnant women. Studies were heterogeneous as to populations selected, processing of specimens and presentation of results. Mercury concentrations of over 50 ng/g were found in China (Shanghai), Japan and the Faroe Islands. Cadmium levels ranged from 1.2 ng/g to 53 ng/g, and were highest in USA, Japan and Eastern Europe. Lead showed the greatest variability, with levels ranging from 1.18 ng/g in China (Shanghai) to 500 ng/g in a polluted area of Poland.

Conclusion: The use of the placenta to assess heavy metals exposure is underdeveloped. International standardized protocols are needed to enhance comparability and increase the usefulness of this promising tissue in biomonitoring studies.

Background: Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase, the gene responsible for nitric oxide production, may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze.

Objectives: To investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children.

Methods: Based on residential address and buccal sample collection date, 7 day, 1 month, 6 month and 1 year cumulative average PM_2.5 and PM₁₀ exposures were estimated for 940 participants in the Children’s Health Study. Methylation of 12 CpG sites in 3 NOS genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, % DNA methylation, and respiratory outcomes.

Results: A 5 µg/m³ increase in PM_2.5 was associated with a 0.20% (95% CI -0.32, -0.07) to 1.0% (95% CI -1.61, -0.56) lower DNA methylation at NOS2A Position 1, 0.06% (95% CI -0.18, 0.06) to 0.58% (95% CI -1.13, -0.02) lower methylation at Position 2, and 0.34% (95% CI -0.57, -0.11) to 0.89% (95% CI -1.57, -0.21) lower methylation at Position 3, depending on the length of exposure and CpG locus. One year PM_2.5 exposure was associated with 0.33% (95% CI 0.01, 0.65) higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5 µg/m³ increase in 7 day and 1 year PM_2.5 was associated with 0.6% (95% CI 0.13, 0.99) and 2.8% (95% CI 1.77, 3.75) higher NOS3 DNA methylation. No associations were observed for NOS1. PM₁₀ showed similar but weaker associations with DNA methylation in these genes.

Conclusions: PM_2.5 exposure was associated with % DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide.