Adipose Tissue Redox Microenvironment as a Potential Link between Persistent Organic Pollutants and the 16-Year Incidence of Non-hormone-Dependent Cancer

We aimed to assess the relationships among the adipose tissue’s (AT) oxidative microenvironment, in situ accumulated persistent organic pollutant (POP) concentrations, and cancer development. POP and oxidative stress levels were quantified in AT samples from 382 adults recruited within the GraMo cohort (2003–2004) in Granada (Spain). The 16-year cancer incidence was ascertained by reviewing health/administrative databases. Cox-regression models and mediation analyses were performed. The enzymes superoxide dismutase (SOD) and glutathione reductase (GRd) were positively associated with the risk of non-hormone-dependent (NHD) cancer [adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI): 1.17, 2.64 and HR 2.35; 95% CI: 1.41, 3.94, respectively]. After adjustment for covariates, polychlorinated biphenyl-138 (PCB-138) (HR 1.78; 95% CI: 1.03, 3.09), β-hexachlorocyclohexane (β-HCH) (HR 1.70; 95% CI: 1.09, 2.64), and hexachlorobenzene (HR 1.54; 95% CI: 1.02, 2.33) were also positively associated with the risk of NHD cancer. Although confidence intervals included the null value, probably because of the modest number of cancer cases, we observed a potential mediation effect of SOD and GRd on the associations between β-HCH and the risk of NHD tumors (percent mediated = 33 and 47%, respectively). Our results highlight the relevance of human AT’s oxidative microenvironment as a predictor of future cancer risk as well as its potential mediating role on POP-related carcinogenesis. Given their novelty, these findings should be interpreted with caution and confirmed in future studies.


Supplemental
. Comparison of sociodemographic and exposure characteristics between participants with both adipose tissue POPs and oxidative stress (OS) biomarkers (n=247) and those with POPs but without OS (n=101).
b Measurement only available in 209 study participants (113 men and 96 women).

Supplemental Table 5. Sex-stratified Cox-regression analyses showing longitudinal associations between adipose tissue levels of persistent organic pollutants and the 16-year incidence of total and non-hormone dependent cancers in GraMo cohort (n=348).
Women ( semi-rural) and education (lower than primary education, primary education or higher than primary). a All incident cases of cancer (n=44), excluding benign tumors and basal cell carcinomas (BCCs). Rest of the study population (n=304). b Non-hormone dependent (NHD) cancers (n=27), excluding hormone-dependent (HD) cancers (n=17). Rest of the study population (n=304). c Participants with concentrations above the limit of detection were compared to those with non-detected concentrations. Non-hormone dependent (NHD) cancers (n=17), excluding hormone-dependent cancers (n=6) from the analysis.

Supplemental Table 7. Mediation analysis. Effect estimates (95% CIs) of each natural logunit increase in adipose tissue POP concentrations and the estimated percentage mediated by selected in situ oxidative stress biomarkers on the risk of non-hormone dependent cancers, without adjustment for BMI (n=247
Rest of the study population (n=224). Superoxide dismutase (SOD); glutathione reductase (GRd). Models were adjusted for age (years), sex (male/female), smoking (yes/no), alcohol consumption (yes/no), place of residence (urban vs. semi-rural) and education (lower than primary education, primary education or higher than primary).
a The direct effect, indirect effect, and total effect reflect the natural log Hazard Ratios (HR) and 95% Confidence Intervals (95% CI). The indirect effect represents the mediated effect.

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Supplemental . Models were adjusted for: age (years), sex (male/female), BMI (kg/m 2 ), smoking (yes/no), alcohol consumption (yes/no), place of residence (urban vs. semi-rural), education (lower than primary education, primary education or higher than primary) and reason for surgery (hernias, gallbladder disease, varicose veins and other conditions).
Rest of the study population (n=304). c Participants with concentrations above the limit of detection were compared to those with non-detected concentrations.