P.M. Lind

Circulating levels of persistent organic pollutants associate in divergent ways to fat mass measured by DXA in humans.

BACKGROUND Environmental contaminants have recently been implicated in the pathogenesis of obesity. OBJECTIVE To explore relations between persistent organic pollutants (POPs) and fat mass independently of body stature, using a cross-sectional design. METHODS In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), fat mass was determined in 70-year-old subjects (n=890) by dual-energy X-ray absorptiometry (DXA). The plasma levels of 21 POPs (including 16 PCB congeners, 3 OC pesticides, 1 BDE47, and 1 dioxin) were measured by high resolution chromatography coupled with high resolution mass spectrometry (HRGC/HRMS). RESULTS Lipid-standardized plasma concentrations of octachlorodibenzo-p-dioxin (OCDD), the PCBs 74, 99, 105 and 118, and the pesticides HCB, TNK, and DDE were all positively related to fat mass (p=0.03-0.0001). Subjects in the fifth quintile for PCB 105 showed a mean fat mass that was 4.8 kg more than subjects in the first quintile. On the other hand, the PCBs 156, 157, 169, 170, 180, 189, 194, 206, and 209 were negatively related to fat mass (p=0.0001). For PCB 194, subjects in the fifth quintile showed a mean fat mass that was 10.8 kg less than subjects in the first quintile. Following adjustment for smoking, physical activity, education level, height, lean mass, and gender, these results remained significant (p=0.01-0.0001) except for the PCBs 74 and 99. For some PCBs, the associations vs. fat mass were more pronounced in women than in men. CONCLUSION Plasma concentrations of some pesticides are positively related to fat mass, while divergent associations are seen for the PCBs. These results implicate a complex role of POPs in obesity.

Circulating levels of persistent organic pollutants are related to retrospective assessment of life-time weight change

BACKGROUND Persistent organic pollutants (POPs) have been suggested to be linked to obesity. We have previously shown that less-chlorinated PCBs were positively related to fat mass, while highly-chlorinated PCBs were inversely related to obesity. OBJECTIVE The aim of the present evaluation is to investigate the relationship between retrospective assessed life-time change in body weight (20-70 years) with circulating POP levels measured at age 70 years. METHODS 1016 subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUSs) study. 16 PCBs and 3 OC pesticides were analyzed using HRGC/HRMS. Current body weight was measured and participants self-reported their weight at age 20. RESULTS The average estimated weight change over 50 years was 14.4 kg. Both the sum of OC pesticide concentrations (4.3 kg more weight gain in quintile 5 vs. quintile 1, p<0.0001) and the sum of the less-chlorinated PCBs were positively related to the estimated weight change (3.7 kg more weight gain in quintile 2 vs. quintile 1, non-linear relationship p=0.0015). In contrast, the sum of concentrations of highly-chlorinated PCBs were inversely related to estimated weight change (8.4 kg less weight gain in quintile 5 vs. quintile 1, p<0.0001). CONCLUSION High levels of OC pesticides and the less-chlorinated PCBs at age 70 were associated with a pronounced estimated weight change over the previous 50 years. However, the opposite was seen for highly-chlorinated PCBs. Differences in mode of action, toxicokinetics, non-linear relationships and reverse causation might explain these discrepancies.

Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A

Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

Expression of the Aryl Hydrocarbon Receptor in Growth Plate Cartilage and the Impact of Its Local Modulation on Longitudinal Bone Growth

Although dioxin has been reported to impair bone growth in both humans and animals, the underlying mechanisms have not been clarified. We conducted this study to rule out if dioxin may directly target the growth plate, via local modulation of the aryl hydrocarbon receptor (AhR). Initial studies in rare tissue samples of the human growth plate confirmed that the AhR protein is widely expressed in growth plate cartilage. To explore the local role of the AhR, mechanistic studies were performed in a well-established model of cultured fetal rat metatarsal bones. The longitudinal growth of these bones was monitored while being exposed to AhR modulators. The AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin, did not affect bone growth at any concentrations tested (1 pM–10 nM). In contrast, the AhR antagonist, alpha-naphthoflavone, suppressed bone growth and increased chondrocyte apoptosis, although only at a high, potentially cytotoxic concentration (50 µM). We conclude that although the AhR is widely expressed in the growth plate, bone growth is not modulated when locally activated, and therefore, dioxin-induced growth failure is likely mediated through systemic rather than local actions.

Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p '-dde levels in a population-based sample

Objectives Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p′-DDE, were related to genome-wide genetic and methylation variation in a population-based sample. Methods In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p,p′-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied. Results Evidence for genome-wide significant association with p,p′-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472 ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192 ng/g lipid (p = 1.5 × 10− 31). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p = 2.2 × 10− 8). A whole-genome methylation analysis showed one significant relationship vs. p,p′-DDE levels (p = 6.2 × 10− 9) located 7 kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p = 3.8 × 10− 35), but mediated only 4% of the effect of the lead SNP on p,p′-DDE levels. Conclusion Circulating levels of p,p′-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p,p′-DDE levels.

The association between p,p′-DDE levels and left ventricular mass is mainly mediated by obesity

Background and objectives The pesticide metabolite p,p′‐DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p′‐DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p′‐DDE with LV mass. Methods p,p′‐DDE was measured in plasma from 70‐year‐old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70‐, 75‐ and 80‐ years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques. Results We found that p,p′‐DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p′‐DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%). Conclusion The obesogenic effect of p,p′‐DDE is a major determinant responsible for the association of p,p′‐DDE with LV mass. Graphical abstract Figure. No Caption available. Highlightsp,p′‐DDE is associated with increased adiposity, glucose, hypertension, and LV mass.The association of p,p′‐DDE with LV mass is primarily mediated by adiposity.The association of p,p′‐DDE with LV mass is also mediated by hypertension.