Impact of AhRR (565C > G) polymorphism on dioxin dependent CYP1A2 induction.

The current study uses the metabolic probe, antipyrine, and AhRR transcript expression (qRT-PCR) to examine the impact of the AhRR (565C > G or Pro185Ala, rs2292596) genetic polymorphism upon CYP1A2 inducibility in an established cohort of male firefighters with exposure to dioxin-like chemicals. The lipid adjusted concentrations of 29 dioxin and dioxin-like congeners were measured in serum. Possession of the G allele (CG and GG genotypes) was correlated with high expression AhRR transcript and lower CYP1A2 induction than found in individuals homozygous for CC. The induction of CYP1A2 was dioxin-dependent among carriers of the G allele. Multivariate models indicated that CYP1A2 activity, detected as urinary 3-hydroxymethylantipyrine, was significantly correlated with cotinine concentration and for those currently working as firefighters, dioxin body burden (ß = 0.54, p = 0.041). The efficacy of the AhRR in regulating the AhR signaling pathway is influenced by the AhRR (565C > G) polymorphism. Our study of firefighters using the induction of CYP1A2 as an indicator suggest that G allele proteins have variable AhR repressor activity which is manifested in a dioxin-dependent manner. These results provide evidence of metabolic differences that may affect susceptibility to dioxin-mediated health effects.

Impact of dioxins on antipyrine metabolism in firefighters.

Antipyrine (AP) metabolism was used to assess factors associated with the activity of hepatic oxidative enzymes in firefighters. Emphasis was placed on 3-hydroxymethylantipyrine (3HMAP), the metabolite with the greatest dependence on dioxin-inducible cytochrome P4501A2 (CYP1A2) activity. AP urinary metabolites were measured by HPLC in 38 male subjects from Eastern Siberia. Subjects were divided into three groups having similar ages and BMIs: current firefighters (n=11); former firefighters (n=17) and non-firefighters (n=10). Multiple regression models were constructed using the three major AP metabolites as a dependent variable to assess the influence of age, smoking as urinary cotinine concentration, dioxin exposure (as either WHO-TEQ or body burden), group, and CYP1A2*F (-163C>A) genotypes. Models for the proportion of dose excreted as the metabolite 3HMAP produced the best fit (adjusted R(2)=0.46, p<0.05). When the models were restricted to current firefighters, only those based on 3HMAP were statistically significant (adjusted R(2) of 0.80 (p<0.002)) due to contributions from urinary cotinine (ß=0.56, p<0.01) and dioxin expressed as body burden (ß=0.55, p=0.014). These results indicate that the antipyrine test can be used as metabolic probe of biological response to recent dioxin exposure provided the impact of smoking is carefully controlled.

Identifying individual risk factors and documenting the pattern of heat-related illness through analyses of hospitalization and patterns of household cooling.

BACKGROUND: As climate change increases the frequency and intensity of extreme heat events researchers and public health officials must work towards understanding the causes and outcomes of heat-related morbidity and mortality. While there have been many studies on both heat-related illness (HRI), there are fewer on heat-related morbidity than on heat-related mortality. OBJECTIVE: To identify individual and environmental risk factors for hospitalizations and document patterns of household cooling. METHODS: We performed a pooled cross-sectional analysis of secondary U.S. data, the Nationwide Inpatient Sample. Risk ratios were calculated from multivariable models to identify risk factors for hospitalizations. Hierarchical modeling was also employed to identify relationships between individual and hospital level predictors of hospitalizations. Patterns of air conditioning use were analyzed among the vulnerable populations identified. RESULTS: Hospitalizations due to HRI increased over the study period compared to all other hospitalizations. Populations at elevated risk for HRI hospitalization were blacks, males and all age groups above the age of 40. Those living in zip-codes in the lowest income quartile and the uninsured were also at an increased risk. Hospitalizations for HRI in rural and small urban clusters were elevated, compared to urban areas. CONCLUSIONS: Risk factors for HRI include age greater than 40, male gender and hospitalization in rural areas or small urban clusters. Our analysis also revealed an increasing pattern of HRI hospitalizations over time and decreased association between common comorbidities and heat illnesses which may be indicative of underreporting.

PCDD, PCDF, and PCB exposure in current and former firefighters from Eastern Siberia.

The current study examines whether the occupation of firefighting contributes to exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCBs). We compared serum dioxin concentrations and congener profiles of current firefighters (n=13) with those of men who have ceased employment as firefighters (n=17) and with men employed in occupations other than firefighter (n=10). We found that compared to former or non-firefighters, current firefighters have higher levels of dioxins primarily due to the contribution of PCBs and to a lesser extent PCDFs. PCDFs were significantly higher in former firefighters compared to non-firefighters (p<0.05). Comparisons with studies performed by other investigators suggest that local environmental conditions contribute to some of the elevation of PCBs. The congeners 1,2,3,4,6,7,8-heptachlorodibenzodioxin and PCB-114 were significantly higher in current firefighters when compared to former or non-firefighters. Moreover, levels of these congeners were inversely correlated with years since employed as firefighter (Spearman r=-0.610, p=0.009 and Spearman r=-0.53, p=0.03, respectively). The classes of dioxins show an overall decline with years since employed as firefighters, this decline is most evident with PCDDs (Spearman r=-0.46, p=0.06). Together, the combination of evidence supports firefighting as a source of exposure to dioxins.

Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: a population-based study in Seveso, Italy.

Approximately 20 years after the Seveso, Italy accident, we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r=-0.35; P = 0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P=0.03). When mitogen-induced lymphocytes were cultured with 10nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another. Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident.