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Objective: The aim of this paper is to propose a new hypothesis for the role of lipophilic chemical mixtures stored in adipose tissue in the development of dementia. Specifically, we present how the dynamics of these chemicals can explain the unexpected findings from the Action for Health in Diabetes (Look AHEAD) study, which failed to show long-term benefits of intentional weight loss on cognition, despite substantial improvements in many known risk factors for dementia. Moreover, we discuss how the role of obesity in the risk of dementia can change depending on the dynamics of these chemicals in adipose tissue., New Hypothesis: Human adipose tissue is widely contaminated with various neurotoxic chemicals. Typical examples are persistent organic pollutants (POPs), strong lipophilic chemicals with long half-lives. Both unintentional and intentional weight loss increases the release of POPs from adipocytes into the circulation. As POPs in the blood can easily reach the brain, the intentional weight-loss group of the Look AHEAD study may have experienced an unappreciated and long-term disadvantage on their cognition. Additionally, POPs may be involved in the link between obesity and dementia, as dysfunctional hypertrophic adipocytes enhance the release of POPs from adipocytes to the circulation through uncontrolled lipolysis. In contrast, metabolically healthy obese people may have a low risk of dementia because the safe storage of POPs in adipose tissue would decrease the amount of POPs reaching the brain., Major Challenges for the Hypothesis: In human studies, there are practical difficulties involved with measuring POPs in the blood, including high costs and complex assays. As the serum concentrations of POPs are continuously affected by weight loss and gain, prospective studies may require serial measurements of POPs. In in-vitro and in-vivo experimental studies, how to simulate the exposure dose, duration, and mixture patterns in humans would be critical., Linkage to Other Major Theories: Even though POPs are direct neurotoxins at a high dosage, low-dose POPs are mitochondrial toxins. Therefore, chronic exposure to low-dose POPs is linked to known key interrelated mechanisms in the pathogenesis of dementia, such as mitochondrial dysfunction and neuroinflammation., (© 2020 the Alzheimer's Association.)

Intentional weight loss can increase health risk in the long‐term, despite short‐term benefits, because human adipose tissue is widely contaminated with various lipophilic environmental contaminants, especially persistent organic pollutants (POPs). Recently, chronic exposure to low POPs has emerged as a new risk factor for common metabolic diseases and cardiovascular diseases. The amount of POPs released from adipocytes to the circulation increases during weight loss, thereby increasing POPs exposure of other critical organs. Possible harmful effects due to release of POPs during weight loss are opposite to those usually expected from losing weight. It is speculated that this tradeoff can explain recent puzzling findings on intensive weight loss. The presence of POPs in adipose tissue adds a challenge to weight management and an optimal strategy of weight management needs to consider both fat mass and dynamics of POPs. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper is to propose a new hypothesis for the role of lipophilic chemical mixtures stored in adipose tissue in the development of dementia. Specifically, we present how the dynamics of these chemicals can explain the unexpected findings from the Action for Health in Diabetes (Look AHEAD) study, which failed to show long‐term benefits of intentional weight loss on cognition, despite substantial improvements in many known risk factors for dementia. Moreover, we discuss how the role of obesity in the risk of dementia can change depending on the dynamics of these chemicals in adipose tissue. New hypothesis: Human adipose tissue is widely contaminated with various neurotoxic chemicals. Typical examples are persistent organic pollutants (POPs), strong lipophilic chemicals with long half‐lives. Both unintentional and intentional weight loss increases the release of POPs from adipocytes into the circulation. As POPs in the blood can easily reach the brain, the intentional weight‐loss group of the Look AHEAD study may have experienced an unappreciated and long‐term disadvantage on their cognition. Additionally, POPs may be involved in the link between obesity and dementia, as dysfunctional hypertrophic adipocytes enhance the release of POPs from adipocytes to the circulation through uncontrolled lipolysis. In contrast, metabolically healthy obese people may have a low risk of dementia because the safe storage of POPs in adipose tissue would decrease the amount of POPs reaching the brain. Major challenges for the hypothesis: In human studies, there are practical difficulties involved with measuring POPs in the blood, including high costs and complex assays. As the serum concentrations of POPs are continuously affected by weight loss and gain, prospective studies may require serial measurements of POPs. In in‐vitro and in‐vivo experimental studies, how to simulate the exposure dose, duration, and mixture patterns in humans would be critical. Linkage to other major theories: Even though POPs are direct neurotoxins at a high dosage, low‐dose POPs are mitochondrial toxins. Therefore, chronic exposure to low‐dose POPs is linked to known key interrelated mechanisms in the pathogenesis of dementia, such as mitochondrial dysfunction and neuroinflammation. [ABSTRACT FROM AUTHOR]

Low dose persistent organic pollutants (POPs) have emerged as a new risk for type 2 diabetes (T2D). Despite substantial evidence from human and experimental studies, there are several critical issues which have not been properly addressed by POPs researchers. First, as POPs exist as mixtures, findings about POPs from human studies should be interpreted from the viewpoint of lipophilic chemical mixtures which include both measured and unmeasured POPs. Second, as POPs can directly reduce insulin secretion of beta cells, the role of POPs may be more prominent in the development of beta-cell dysfunction-dominant T2D rather than insulin resistance-dominant T2D. Third, there are multidimensional interrelationships between POPs and adipose tissue. Even though POPs are now considered as a new risk factor for T2D, independent of obesity, POPs and obesity are mechanistically linked to each other. POPs are involved in key mechanisms linking obesity and T2D, such as chronic inflammation of adipose tissue and lipotoxicity with ectopic fat accumulation. Also, POPs can explain puzzling human findings which suggest benefits of obesity because healthy adipose tissue can be protective by reducing the amount of POPs reaching other organs. Fourth, non-linear dose-response relationships between POPs and T2D are biologically possible. Although POPs are well-known endocrine disrupting chemicals (EDCs), mitochondrial dysfunction may be a more plausible mechanism due to unpredictability of EDC mixtures. As adipose tissue plays a role as an internal exposure source of POPs, how to manage POPs inside us may be essential to protect against harms of POPs. [ABSTRACT FROM AUTHOR]

Background: Persistent organic pollutants (POPs), despite their considerably low levels in humans, are an increasing concern for the general populations given their various adverse health problems, including metabolic and carcinogenic effects. DNA methylation deregulation is thought to be a key mechanism in the development of human chronic diseases including cancer. Methods: In an attempt to identify biomarkers monitoring low-dose exposure and hazard, we explored whether organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) may influence the methylation of tumour suppressor gene E-cadherin (CDH1) using peripheral blood cells from 364 healthy Korean subjects. Results: CDH1 methylation was observed in 78.3% of study subjects. Serum concentrations of OCPs or PCBs compounds were higher in CDH1 methylation-positive subjects than in methylation-negative ones. After adjusting for various covariates, the odds ratio of CDH1 methylation of the summary measure of PCBs were 1.0, 2.5 (95% confidence interval: 1.2-5.3), 3.6 (1.6-8.1), 3.6 (1.4-8.6), and 2.5 (1.1-5.7) across quintiles of PCBs (Ptrend = 0.01). The values of OCPs were 1.0, 0.9, 1.2, 2.4 (1.0-5.9), and 1.7 (Ptrend = 0.05). Conclusions: In this exploratory study with a small sample, CDH1 methylation might be served as the epigenetic biomarker associated with POPs exposure and adverse health effect. [ABSTRACT FROM AUTHOR]

Although the toxicity of synthetic chemicals at high doses is well known, chronic exposure to low-dose chemical mixtures has only recently been linked to many age-related diseases. However, it is nearly impossible to avoid the exposure to these low-dose chemical mixtures as humans are exposed to a myriad of synthetic chemicals as a part of their daily lives. Therefore, coping with possible harms due to low dose chemical mixtures is challenging. Interestingly, within the range of environmental exposure, disease risk does not increase linearly with increasing dose of chemicals, but often tends to plateau or even decrease with increasing dose. Hormesis, the over-compensation of various adaptive responses through cellular stresses, is one possible mechanism for this non-linearity. Although the hormetic effects of synthetic chemicals or radiation have long been debated in the field of toxicology, the hormesis concept has recently been generalized in the field of molecular biology; similar to responses to synthetic chemicals, mild to moderate intermittent stressors from any source can induce hormetic responses. Examples of stressors are exercise, calorie restriction, intermittent fasting, cognitive stimulation, and phytochemicals. Mitohormesis is hormesis induced by such stressors through mitochondrial retrograde signalling including the increased production of mild reactive oxygen species. Xenohormesis is phytochemical-induced hormesis, reflective of a mutualistic relationship between plant and animals. As humans had repeated exposure to all of these stressors during their evolution, the hormetic effects of these health behaviours may be considered to be evolutionarily adapted. Although hormesis induced by synthetic chemicals occurs in humans, such hormesis may not be recommended to the public due to unresolved issues on safety including the impossibility of control exposure. However, the use of personal health behaviors which enhance mitohormetic- or xenohormetic-stress can be readily incorporated into everyone's daily lives as a practical way to counteract harmful effects of unavoidable low-dose chemical mixtures. [ABSTRACT FROM AUTHOR]

The Halifax project recently hypothesized a composite carcinogenic potential of the mixture of low dose chemicals which are commonly encountered environmentally, yet which are not classified as human carcinogens. A long neglected but important fact is that adipose tissue is an important exposure source for chemical mixtures. In fact, findings from human studies based on several persistent organic pollutants in general populations with only background exposure should be interpreted from the viewpoint of chemical mixtures because serum concentrations of these chemicals can be seen as surrogates for chemical mixtures in adipose tissue. Furthermore, in conditions such as obesity with dysfunctional adipocytes or weight loss in which lipolysis is increased, the amount of the chemical mixture released from adipose tissue to circulation is increased. Thus, both obesity and weight loss can enhance the chance of chemical mixtures reaching critical organs, however paradoxical this idea may be when fat mass is the only factor considered. The complicated, interrelated dynamics of adipocytes and chemical mixtures can explain puzzling findings related to body weight among cancer patients, including the obesity paradox. The contamination of fat in human diet with chemical mixtures, occurring for reasons similar to contamination of human adipose tissue, may be a missing factor which affects the association between dietary fat intake and cancer. The presence of chemical mixtures in adipose tissue should be considered in future cancer research, including clinical trials on weight management among cancer survivors. [ABSTRACT FROM AUTHOR]

Background Background exposure to organochlorine (OC) pesticides was recently linked to cognitive impairment and dementia in cross-sectional and case–control studies. This prospective study was performed to evaluate if OC pesticides at baseline are associated with the future risk of cognitive impairment in elderly, with particular focus on weight change. Methods Plasma concentrations of 3 OC pesticides (p,p′-DDE, trans-nonachlor, and hexachlorobenzene) were measured among 989 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Cognitive impairment was validated by reviewing medical records. During the ten year follow-up, cognitive impairment was developed in 75 subjects. When weight change from age 70 to 75 was considered in analyses, elderly with incident cases before age 75 were excluded to keep the prospective perspective, leaving 795 study subjects and 44 incident cases. Results The summary measure of 3 OC pesticides predicted the development of cognitive impairment after adjusting for covariates, including weight change. Compared to subjects with OC pesticides < 25th percentile, adjusted hazard ratios (HRs) in those with 25th–<75th and ≥ 75th percentiles were 3.5 (95% confidence interval: 1.5–8.5) and 3.2 (1.1–7.6), respectively (P trend = 0.04). Among 506 subjects who maintained or gained body weight, adjusted HRs were 6.9 and 11.6 (1.4–92.6) among the elderly in the 25th–<75th and ≥ 75th percentiles compared to < 25th percentile (P trend < 0.01). Conclusions This prospective study demonstrates that background exposure to OC pesticides are linked to the risk of developing cognitive impairment in elderly. The role of the chronic exposure to low dose OC pesticides in the development of dementia should be further evaluated in other populations. [ABSTRACT FROM AUTHOR]

Promoter hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair gene is important during carcinogenesis. We explored whether organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), were associated with hypermethylation of the MGMT gene promoter in peripheral leukocytes among 368 Koreans without cancer. Hypermethylation decreased as OCPs increased (Ptrend = 0.02), while PCB concentrations showed an inverted U-shaped association (Pquadratic < 0.01). The prevalence of MGMT promoter hypermethylation was highest within the 2nd quintile of the PCB summary score (28.4%), while it was only 2.7% in the upper 10% score. Chronic exposure to these chemicals may affect methylation of the MGMT promoter, with possibly non-monotonic dose response relationships. [ABSTRACT FROM AUTHOR]

Abstract: 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 (20–70years) with circulating POP levels measured at age 70years. Methods: 1016 subjects aged 70years 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 50years was 14.4kg. Both the sum of OC pesticide concentrations (4.3kg 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 (3.7kg 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 (8.4kg 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 50years. 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. [Copyright &y& Elsevier]

Abstract: Background exposure to persistent organic pollutants (POPs), lipophilic xenobiotics that accumulate mainly in adipose tissue, has recently emerged as a new risk factor for cardiovascular diseases. This prospective study was performed to evaluate if plasma concentrations of selected POPs predict incident stroke among the elderly. Twenty‐one POPs (including 16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured in plasma collected at baseline in 898 participants aged 70years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Stroke diagnosis was validated by hospital records. During the five year follow-up, 35 subjects developed hospital-treated stroke. After adjusting for known stroke risk factors, most PCBs with 4, 5, or 6 chlorine atoms, p,p′-DDE, trans-nonachlor, and octachlorodibenzo-p-dioxin significantly predicted the risk of stroke. Across quartiles of summary measures of PCBs and OC pesticides, the adjusted ORs were 1.0, 0.8 (95% confidence interval: 0.2–2.5), 1.2 (0.4–3.4), and 2.1 (0.7–6.2) for PCBs and 1.0, 1.2 (0.3–4.2), 2.3 (0.7–6.9), and 3.0 (1.0–9.4) for OC pesticides (P for trend=0.11 and 0.03, respectively). The adjusted ORs among participants ≥90th percentile of the summary measures were 5.5 (1.7–18.1) for PCBs and 4.0 (1.1–14.6) for OC pesticides; corresponding ORs for those ≥95th percentile were 7.8 (2.1–29.6) and 9.5 (2.3–38.9). Background exposure to POPs may play an important role in development or progression of stroke in the elderly. [Copyright &y& Elsevier]

Abstract: Objectives: In animal experiments, persistent organic pollutants (POPs) have induced visceral obesity. To address this possibility in humans, we evaluated associations between POPs and abdominal obesity both cross-sectionally and prospectively. Methods: Twenty-one plasma POPs (16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured at baseline in 970 participants aged 70years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), with prospective analyses in 511 participants re-examined after 5years. Abdominal obesity was defined by an increased waist circumference. Results: In the cross-sectional analyses, concentrations of the less chlorinated PCBs, OC pesticides such as p,p′-DDE and dioxin had adjusted odds ratios of 2 to 3 for abdominal obesity. Many relations had inverted U-shapes rather than being linear, particularly in women. In contrast, concentrations of highly chlorinated PCBs were strongly inversely associated with abdominal obesity. In a single model including summary measures of the less chlorinated PCBs, highly chlorinated PCBs, and OC pesticides, both the positive associations and inverse associations strengthened. Similar but somewhat weaker associations were seen between POPs and risk of development of abdominal obesity in the prospective analyses. Conclusion: Using both a cross-sectional and a prospective design, low-dose exposure to less chlorinated PCBs, p,p′-DDE, and dioxin, were associated with existence or development of abdominal obesity, while highly chlorinated PCBs had an opposite association in an elderly population, despite the previous observation of higher incident diabetes associated with these same PCBs. [Copyright &y& Elsevier]

Epidemiologic studies have indicated that albuminuria is associated with mortality from all causes and cardiovascular disease (CVD), with substantial heterogeneity. We evaluated if the associations of urine albumin creatinine ratio (ACR) with all-cause and CVD mortality differed depending on serum concentrations of persistent organic pollutants (POPs), strong lipophilic chemical mixtures with very long half-lives, which are recently linked to many degenerative diseases. Study subjects were participants of the National Health and Nutrition Examination Survey 1999–2004 who were 60 years or older at baseline (n=1215 and 1067 for organochlorine pesticides (OCPs) and other POPs, respectively). They were followed-up through 2011 (mean follow-up periods: 8.1 and 8.0 years for OCPs and other POPs, respectively). The associations between the ACR and all-cause mortality significantly differed by the serum levels of POPs, especially organochlorine pesticides (OCPs; P interaction <0.01). Stratified analyses indicated that the associations between ACR and all-cause mortality became stronger as the serum levels of OCPs increased. Among the elderly with the highest tertile of OCPs, the adjusted hazard ratios were 1.0, 1.1, and 2.9 (P trend <0.01) across the categories of ACR (<10, 10–<30, and ≥30 mg/g); however, ACR was not clearly related to mortality among the elderly with the lowest tertile of OCPs. CVD mortality showed similar interactions, as noted for all-cause mortality (P interaction <0.01). The different associations between albuminuria and mortality by the serum OCP levels and the little association among the elderly with low serum OCPs levels suggest that OCPs play an important role in albuminuria-related death risk. However, these findings need to be replicated in other cohort studies. [ABSTRACT FROM AUTHOR]

Background We investigated if certain persistent organic pollutants (POPs), namely polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides, predicted total, cardiovascular disease (CVD), and cancer mortality among the elderly, with the hypothesis that associations differ by the amount of fat mass. Methods We studied serum concentrations of 11 PCBs in 633 elders (age≥70 years) and of 5 OC pesticides in 675 elders within the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Mean follow-up was 4.1-years. Results Neither PCBs nor OC pesticides were associated with total mortality when fat mass was not considered in analyses. However, associations of PCBs and OC pesticides with total mortality depended on fat mass ( P interaction <0.01 and 0.06, respectively). PCBs associated inversely with total mortality for high fat mass, but not for lower fat mass. On the contrary, OC pesticides associated positively with total mortality for low fat mass and this association weakened at higher fat mass. The interaction was also observed with CVD mortality. In elders with low fat mass, higher PCBs associated with 2–3 fold higher risk of CVD mortality, while this association was absent in elders with more fat mass ( P interaction =0.03). The positive association between OC pesticides and CVD mortality was also observed only among elderly with low fat mass ( P interaction =0.03). Conclusions The possibility of interaction between POPs and the amount of fat mass on risk of mortality from chronic diseases is clinically important in modern societies with an obesity epidemic and requires confirmation in other studies with larger sample size. [ABSTRACT FROM AUTHOR]

Objective Exposure to persistent organic pollutants (POPs) has recently been linked to metabolic syndrome (MetS) and some MetS components. However, prospective evidence in humans is scarce, and the nature of the dose–response relationship is unclear. We evaluated the association between POPs and MetS using a nested-case control study within a community-based Korean cohort. Method The study subjects were 64 patients newly diagnosed with MetS during a 4-year follow-up, and the controls were 182 subjects without MetS. Concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were measured in stored serum collected at baseline. Results The concentrations of most PCBs and some OCPs such as β-hexachlorocyclohexane, hexachlorobenzene, oxychlordane, and heptachlor epoxide predicted the risk for MetS. The POP exposure and MetS showed an inverted U-shaped or a linear association with plateau rather than a linear dose–response association. When the summary measure of the PCBs and OCPs was used, the adjusted odds ratios (ORs) across the quartiles of the summary measure were 1.0, 1.3, 3.8 (95% confidence interval, 1.3–10.7), and 2.1 (P quadratic = 0.013) after adjusting for potential confounders. In the analyses of each of the five MetS components, POP exposure was mainly associated with an increased risk for glucose and lipid metabolism disturbances. Conclusion This study demonstrated that chronic exposure to a mixture of PCBs and OCPs can increase the risk for MetS within the low-dose background exposure range of POPs. As the findings of this study suggest a nonmonotonic dose–response relationship, in vitro and in vivo experimental studies are needed to understand the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Background: Background exposure to persistent organic pollutants (POPs) has emerged as a new risk factor for metabolic syndrome (MetS), while hyperuricemia is associated with MetS through unclear mechanisms. Objective: We examined cross-sectional data for consistency with the hypothesis that POPs are a common underlying risk factor of both MetS and hyperuricemia. Methods: We evaluated associations of POPs with hyperuricemia in subjects aged ≥20 years in the population-based National Health and Nutrition Examination Survey (NHANES) 2003–2004. Sample size was n = 1331 for organochlorine (OC) pesticides and n = 1299 for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Results: Among all subjects, the risk of hyperuricemia was higher for higher serum concentrations of OC pesticides, PCDDs, and dioxin-like PCBs. PCDFs and nondioxin-like PCBs did not show any clear trend. Adjusted odds ratios (ORs) for OC pesticides, PCDDs, and dioxin-like PCBs were 1.0, 2.4, 2.3, 3.0, and 2.5 (P trend = 0.05), 1.0, 1.6, 1.4, 2.1, and 2.5 (P trend = 0.01), and 1.0, 1.3, 1.4, 1.3, and 2.4 (P trend = 0.04). When we restricted the analyses to subjects without MetS, all these associations appeared to strengthen. Conclusion: This study is consistent with our hypothesis that the risk of hyperuricemia relates to background exposure to a mixture of POPs even among persons without MetS. There should be further research about whether avoiding exposure to POPs and otherwise decreasing body burden of POPs would be helpful to prevent or manage hyperuricemia or gout. [Copyright &y& Elsevier]