P. Monica Lind

Polychlorinated Biphenyls and Organochlorine Pesticides in Plasma Predict Development of Type 2 Diabetes in the Elderly The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

OBJECTIVE Persistent organic pollutants (POPs), lipophilic chemicals that accumulate mainly in adipose tissue, have recently been linked to type 2 diabetes. However, evidence from prospective studies is sparse. This study was performed to evaluate prospective associations of type 2 diabetes with selected POPs among the elderly. RESEARCH DESIGN AND METHODS Nineteen POPs (14 polychlorinated biphenyl [PCB] congeners, 3 organochlorine pesticides, 1 brominated diphenyl ether, and 1 dioxin) were measured in plasma collected at baseline in 725 participants, aged 70 years, of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). RESULTS After adjusting for known type 2 diabetes risk factors, including obesity, odds ratios (ORs) (95% CIs) for type 2 diabetes at age 75 years (n = 36) according to the quintiles of a summary measure of concentrations of PCBs (vs. the lowest quintile) were 4.5, 5.1, 8.8 (1.8–42.7), and 7.5 (1.4–38.8) (Ptrend <0.01). Among organochlorine pesticides, adjusted ORs across concentrations of trans-nonachlor showed that Ptrend = 0.03. Adjusted ORs (95% CIs) across quintiles of the sum of three organochlorine pesticides were 1.1, 1.6, 1.5, and 3.4 (1.0–11.7) (Ptrend = 0.03). Neither brominated diphenyl ether 47 nor dioxin was significantly associated with incident diabetes. The sum of PCBs improved reclassification significantly when added to traditional risk factors for diabetes. CONCLUSIONS Despite the small number of incident cases, this study found that environmental exposure to some POPs substantially increased risk of future type 2 diabetes in an elderly population.

CIRCULATING LEVELS OF BISPHENOL A AND PHTHALATES ARE RELATED TO CAROTID ATHEROSCLEROSIS IN THE ELDERLY

BACKGROUND AND OBJECTIVE Bisphenol A (BPA) levels have previously been associated with coronary heart disease (CHD). Since CHD is an atherosclerotic disease, we investigated if circulating levels of BPA and phthalate metabolites are related to atherosclerosis in a cross-sectional study. METHODS In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), the prevalence of overt plaques and echogenectity (grey scale median, GSM) of carotid artery plaques were recorded by ultrasound in both of the carotid arteries. The thickness (IMT) and echogenicity (IM-GSM) of the intima-media complex were also measured. Bisphenol A (BPA) and 10 phthalate metabolites were analyzed in serum by a API 4000 liquid chromatograph/tandem mass spectrometer. RESULTS Mono-methyl phthalate (MMP) was related to carotid plaques in an inverted U-shaped manner. This pattern was significant after adjustment for gender, body mass index, blood glucose, blood pressure, HDL and LDL-cholesterol, serum triglycerides, smoking, antihypertensive treatment and statin use (p=0.004). High levels of BPA, mono-isobutyl phthalate (MiBP) and MMP were associated with an echogenic IM-GSM and plaque GSM, while high levels of mono-2-ethylhexyl phthalate (MEHP) were associated with an echolucent IM-GSM and plaque GSM (p<0.0001 after adjustment). CONCLUSION The phthalate metabolite MMP was related to atherosclerotic plaques in an inverted U-shaped manner independently of CV risk factors. Some phthalates and BPA were also related to the echogenicity of the plaques, suggesting a role for plaque-associated chemicals in atherosclerosis.

Circulating Levels of Phthalate Metabolites Are Associated With Prevalent Diabetes in the Elderly

OBJECTIVE Phthalates are ubiquitous industrial high-volume chemicals known as ligands to peroxisome proliferator–activated receptors (PPARs). Because PPAR-γ agonists modulate insulin sensitivity and are used to treat type 2 diabetes, we investigated whether circulating levels of phthalate metabolites are related to prevalent type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 1,016 subjects, aged 70 years, were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors Study. Four phthalate metabolites were detected in almost all participant sera by an API 4000 liquid chromatograph/tandem mass spectrometer. Type 2 diabetes was defined as the use of pharmacological hypoglycemic agents or a fasting plasma glucose >7.0 mmol/L. RESULTS A total of 114 subjects were shown to have diabetes. Following adjustment for sex, BMI, serum cholesterol and triglycerides, educational level, and smoking and exercise habits, high levels of the phthalate metabolites monomethyl phthalate (MMP) (P < 0.01), monoisobutyl phthalate (MiBP) (P < 0.05), and monoethyl phthalate (MEP) (P < 0.05), but not mono(2-ethylhexyl) phthalate, were associated with an increased prevalence of diabetes. Using the fasting proinsulin–to–insulin ratio as a marker of insulin secretion and the homeostasis model assessment-insulin resistance index as a marker of insulin resistance, MiBP was mainly related to poor insulin secretion, whereas MEP and MMP mainly were related to insulin resistance. CONCLUSIONS The findings in this cross-sectional study showed that several phthalate metabolites are related to diabetes prevalence, as well as to markers of insulin secretion and resistance. These findings support the view that these commonly used chemicals might influence major factors that are regulating glucose metabolism in humans at the level of exposure of phthalate metabolites seen in the general elderly population.

Circulating Levels of Persistent Organic Pollutants (POPs) and Carotid Atherosclerosis in the Elderly

Background and objective: Increased circulating levels of persistent organic pollutants (POPs) have been associated with myocardial infarction. Because myocardial infarction is an atherosclerotic disease, we investigated, in a cross-sectional study, whether POP levels are related to atherosclerosis. Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1,016 participants 70 years of age), the prevalence of carotid artery plaques was determined by ultrasound. The number of carotid arteries with plaques (0, 1, or 2) was recorded. Also, the intima-media thickness (IMT) and gray scale median of the intima-media complex (IM-GSM) were measured. Twenty-three POPs, comprising 16 polychlorinated biphenyls (PCBs), 5 pesticides, 1 dioxin, and 1 brominated compound (brominated diphenyl ether congener BDE-47), were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry. Results: Seven of the POPs (PCB congeners 153, 156, 157, 170, 180, 206, and 209) were significantly associated with the number of carotid arteries with plaques even after adjusting for multiple risk factors (sex, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, high-density lipoprotein and low-density lipoprotein cholesterol, serum triglycerides, smoking, antihypertensive treatment, and statin use; p = 0.002–0.0001). Highly chlorinated PCBs (congeners 194, 206, and 209) were associated with an echolucent IM-GSM (p < 0.0001 after adjustment), whereas associations between POPs and IMT were modest. Conclusions: Circulating levels of PCBs were associated with atherosclerotic plaques and echogenicity of the intima-media complex independent of cardiovascular risk factors, including lipids. This suggests that POPs may be a risk factor for myocardial infarction, but associations need to be confirmed in prospective studies.

Associations between circulating levels of bisphenol A and phthalate metabolites and coronary risk in the elderly

Studies have pointed out associations between various chemicals with estrogenic activity and cardiovascular disease. Being ubiquitous, the plastic additive substances bisphenol A (BPA), and phthalates have been detected in almost all types of analyzed human samples. The aim of this study was to investigate whether circulating levels of BPA and/or four selected phthalate metabolites are associated to coronary risk in an elderly population. In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, coronary risk was assessed by the Framingham Risk Score (FRS) together with circulating serum levels of BPA and the four phthalate metabolites monoisobutyl phthalate (MiBP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-(2-ethylhexyl) phthalate (MEHP) in 1016 subjects aged 70 years. BPA, MEHP, and MMP were associated to LDL-cholesterol and MEHP to HDL-cholesterol, MEP to diastolic blood pressure and MiBP to fasting glucose when the compounds were investigated one by one. After Bonferronni correction, only the relations for MMP to LDL-cholesterol (p<0.0001), MEP to diastolic blood pressure (p<0.0002), and MiBP to fasting glucose (p<0.0001) remained significant. MMP was associated to the FRS (p=0.02), but after Bonferronni correction, this association was not significant. In conclusion, associations were found between MMP and LDL-cholesterol, MEP and diastolic blood pressure, and MiBP and fasting glucose. We did not observe any strong associations between BPA nor any of the four phthalate metabolites and Framingham Risk Score in this elderly population.

Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women

BackgroundPhthalates, commonly used to soften plastic goods, are known PPAR-agonists affecting lipid metabolism and adipocytes in the experimental setting. We evaluated if circulating concentrations of phthalates were related to different indices of obesity using data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Data from both dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) were used.Methods1,016 subjects aged 70 years were investigated in the PIVUS study. Four phthalate metabolites were detected in the serum of almost all subjects (> 96%) by an API 4000 liquid chromatograph/tandem mass spectrometer. Abdominal MRI was performed in a representative subsample of 287 subjects (28%), and a dual-energy X-ray absorptiometry (DXA)-scan was obtained in 890 (88%) of the subjects two year following the phthalate measurements.ResultsIn women, circulating concentrations of mono-isobutyl phthalate (MiBP) were positively related to waist circumference, total fat mass and trunk fat mass by DXA, as well as to subcutaneous adipose tissue by MRI following adjustment for serum cholesterol and triglycerides, education, smoking and exercise habits (all p < 0.008). Mono-methyl phthalate (MMP) concentrations were related to trunk fat mass and the trunk/leg-ratio by DXA, but less powerful than MiBP. However, no such statistically significant relationships were seen in men.ConclusionsThe present evaluation shows that especially the phthalate metabolite MiBP was related to increased fat amount in the subcutaneous abdominal region in women measured by DXA and MRI two years later.

Bone mineral density in male Baltic grey seal (Halichoerus grypus).

Abstract Bone mineral density (mg cm−3) was studied in male Baltic grey seals (4–23 years of age) by noninvasive computed tomography (pQCT). The material was grouped according to year of collection. Group A: 1850–1955, a period before the main introduction of organochlorines (OCs); Group B: 1965–1985, a period with very high OC contamination; and Group C: 1986–1997, a period with decreasing concentrations of OCs. The reproducibility of the measurements was good with a Coefficient of Variation (CV) ranging from 0.1% to 2.1%. Trabecular bone mineral density of the radius was significantly higher in specimens collected 1986–1997 than in those collected 1965–1985 (p < 0.05). Cortical bone mineral density of the mandible was significantly lower in specimens collected 1986–1997 compared with those collected 1850–1955 (p < 0.05). These results indicate different responses over time in trabecular and cortical bone. During the period of very high OC contamination (1965–1985), trabecular bone density was lowest, whereas cortical bone density was lowest in specimens collected 1985–1997, representing a period of fairly low OC contamination. The mechanisms behind these effects are not known. However, it can be assumed that OCs are involved. Information about residue levels of OCs in the studied individuals is lacking and, therefore, it was not possible to evaluate the impact of OCs in this respect.

A rapid method for screening of the Stockholm Convention POPs in small amounts of human plasma using SPE and HRGC/HRMS

A rapid analytical screening method allowing simultaneous analysis of 23 persistent organic pollutants (POPs) in human plasma was developed. Sample preparation based on solid-phase extraction (SPE) with additional clean-up using small multilayer silica gel columns. SPE was performed using a custom made polystyrene-divinylbenzene sorbent for the extraction of chlorinated and brominated POPs. Special efforts to reduce sample volume and improve speed and efficiency of the analytical procedure were made. Determination of 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin (OCDD) and polybrominated diphenyl ether (BDE #47) in 0.5 mL human plasma was performed by using high resolution gas chromatography coupled to high resolution mass spectrometry (HRGC/HRMS). Recovery of POPs ranged between 46% and 110%, and reproducibility was below 25% relative standard deviation (RSD) for all target compounds, except for trans-nonachlor and OCDD, which were present only at low levels. Limits of detection (LOD) were for the PCBs between 0.8 and 117.7 pg mL(-1) plasma and for the OC pesticides between 5.9 and 89.1 pg mL(-1) plasma. The LOD for OCDD and BDE #47 were 1.4 pg mL(-1) plasma, and 9.2 pg mL(-1) plasma, respectively. The presented method was successfully applied to 1016 human plasma samples from an epidemiological study on cardiovascular disease.

Bone mineral density changes in relation to environmental PCB exposure

Background Bone toxicity has been linked to organochlorine exposure following a few notable poisoning incidents, but epidemiologic studies in populations with environmental organochlorine exposure have yielded inconsistent results. Objectives The aim of this study was to investigate whether organochlorine exposure was associated with bone mineral density (BMD) in a population 60–81 years of age (154 males, 167 females) living near the Baltic coast, close to a river contaminated by polychlorinated biphenyls (PCBs). Methods We measured forearm BMD in participants using dual energy X-ray absorptiometry; and we assessed low BMD using age- and sex-standardized Z-scores. We analyzed blood samples for five dioxin-like PCBs, the three most abundant non-dioxin-like PCBs, and p,p′-dichloro-phenyldichloroethylene (p,p′-DDE). Results In males, dioxin-like chlorobiphenyl (CB)-118 was negatively associated with BMD; the odds ratio for low BMD (Z-score less than −1) was 1.06 (95% confidence interval, 1.01–1.12) per 10 pg/mL CB-118. The sum of the three most abundant non-dioxin-like PCBs was positively associated with BMD, but not with a decreased risk of low BMD. In females, CB-118 was positively associated with BMD, but this congener did not influence the risk of low BMD in women. Conclusions Environmental organochlorine exposures experienced by this population sample since the 1930s in Sweden may have been sufficient to result in sex-specific changes in BMD.

Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats

BACKGROUND Prenatal exposure to bisphenol A (BPA) has been shown to induce obesity in rodents. To evaluate if exposure also later in life could induce obesity or liver damage we investigated these hypothesises in an experimental rat model. METHODS From five to fifteen weeks of age, female Fischer 344 rats were exposed to BPA via drinking water (0.025, 0.25 or 2.5 mg BPA/L) containing 5% fructose. Two control groups were given either water or 5% fructose solution. Individual weight of the rats was determined once a week. At termination magnetic resonance imaging was used to assess adipose tissue amount and distribution, and liver fat content. After sacrifice the left perirenal fat pad and the liver were dissected and weighed. Apolipoprotein A-I in plasma was analyzed by western blot. RESULTS No significant effects on body weight or the weight of the dissected fad pad were seen in rats exposed to BPA, and MRI showed no differences in total or visceral adipose tissue volumes between the groups. However, MRI showed that liver fat content was significantly higher in BPA-exposed rats than in fructose controls (p=0.04). BPA exposure also increased the apolipoprotein A-I levels in plasma (p<0.0001). CONCLUSION We found no evidence that BPA exposure affects fat mass in juvenile fructose-fed rats. However, the finding that BPA in combination with fructose induced fat infiltration in the liver at dosages close to the current tolerable daily intake (TDI) might be of concern given the widespread use of this compound in our environment.