Persistent Organic Pollutants in Adipose Tissue Should Be Considered in Obesity Research

obesity reviews doi: 10.1111/obr.12481

Viewpoint Persistent organic pollutants in adipose tissue should be considered in obesity research

Y.-M. Lee,1 K.-S. Kim,1 D. R. Jacobs Jr3 and D.-H. Lee1,2

1Department of Preventative Medicine, School Summary of Medicine, Kyungpook National University, Although low doses of persistent organic pollutants (POPs), strong lipophilic Daegu, Korea, 2BK21 Plus KNU Biomedical chemicals with long half-lives, have been linked to various endocrine, immune, Convergence Program, Department of nervous and reproductive system diseases, few obesity studies have considered Biomedical Science, Kyungpook National adipose tissue as an important POPs exposure source. Because the toxicodynamics University, Daegu, Korea, and 3Division of of POPs relate directly to the dynamics of adiposity, POPs might explain puzzling Epidemiology and Community Health, School findings in obesity research. In two people exposed to the same amounts of of Public Health, University of Minnesota, environmental POPs, the one having more adipose tissue may be advantaged Minneapolis, MN, USA because POPs storage in adipose tissue can reduce burden on other critical organs. Therefore, adipose tissue can play a protective role against the POPs effects. Received 17 August 2016; revised 23 However, two situations increase the POPs release from adipose tissue into the September 2016; accepted 28 September circulation, thereby increasing the risk that they will reach critical organs: (i) weight 2016 loss and (ii) insulin resistance. In contrast, weight gain reduces this possibility. Therefore, avoiding harmful health effects of POPs may mostly contradict conven- Address for correspondence: Duk-Hee Lee, tional judgments about obesity and weight change. These contradictory situations Department of Preventive Medicine, School of can explain the obesity paradox, the adverse effects of intensive intentional weight Medicine, Kyungpook National University, 680 loss and the protective effects of obesity against dementia. Future studies should Gukchaebosang-ro, Jung-gu, Daegu 41944, consider that adipose tissue is widely contaminated with POPs in modern society. Korea. E-mail: [email protected] Keywords: Dementia, obesity paradox, persistent organic pollutants, weight loss.

Persistent organic pollutants contaminate pesticides (OCPs), polychlorinated biphenyls (PCBs) and adipose tissue dioxins (1). Although many researchers consider adipose tissue as a Most OCPs and PCBs were banned several decades ago pure organ consisting of adipocytes, blood vessels and in many countries, and dioxin emission is strictly regulated endogenous molecules, the contemporary view of adipose in most countries. However, humans are still exposed to tissue suggests that it is widely contaminated with various these chemicals through several routes (1). The major man-made lipophilic chemicals, including the by-products source of external exposure to these chemicals is POP- of a wide range of manufacturing processes. The most contaminated food, especially fatty animal products such well-known class of these chemicals is persistent organic pol- as fish, meat and milk (including breast milk) (1,2). An im- lutants (POPs). POPs include several hundred halogenated portant source of internal exposure to these chemicals is compounds with common features such as resistance to bio- POP-contaminated adipose tissue in the body (3,4). When degradation, environmental persistence, bioaccumulation in these chemicals enter the body through breast milk, food the food chain, strong lipophilicity and storage in the adi- or other sources, they are primarily stored in adipose tissue pose tissue of living organisms (1). Typical examples of POPs and slowly released into the circulation to be eliminated include chlorinated compounds such as organochlorine over several years (5).

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Although early toxicological studies indicated that expo- homeostasis in lean mice but not in obese mice; however, sure to high levels of POPs is harmful to human health, it glucose homeostasis was impaired after weight loss in obese was recently observed that chronic exposure to low levels mice (15). Diet-induced obesity in rats after exposure to a of POPs can also adversely affect the endocrine, immune, lethal dose of dioxin increased survival time (16). A recent nervous and reproductive systems (6). In particular, review article expertly discussed the role of adipose tissue substantial epidemiological and experimental evidence has as a protective organ against POPs (17). linked low-dose POP exposure to obesity-related metabolic dysfunctions such as type 2 diabetes and metabolic syndrome (1,7). Situations associated with the increased release Traditional toxicity studies argued that dioxin is the most of persistent organic pollutants from adipose toxic compound among various compounds classified as tissue POPs because of its affinity for the aryl hydrocarbon receptor (8). However, findings from recent human studies have The POPs stored in adipose tissue are slowly released as suggested that the harmful effects of low-dose POPs might they are eliminated from the blood to maintain equilibrium be the result of chronic exposure to mixtures of POPs rather (18). The ratio of the concentration of POPs in adipose than to independent effects of several individual compounds tissue to blood may remain relatively constant. In certain (1,7). Although many in vitro and in vivo toxicological situations, however, the amount of POPs released from studies have been conducted on the effects of exposure to adipose tissue into the circulation increases. Under these high levels of individual POP compounds, only a few exper- conditions, if the body cannot efficiently metabolize and imental studies have explored the effects of chronic expo- eliminate these chemicals, then the circulating POPs have a sure to low levels of POP mixtures, especially in terms of higher chance of reaching critical organs. the dose and duration of exposure in humans (9,10). Many Two common situations occur in which POPs are released individual compounds classified as POPs are well- at a higher rate than normal from adipose tissue into the established endocrine disrupting chemicals (EDCs), and circulation: (1) weight loss and (2) insulin resistance. The chronic glutathione depletion and mitochondrial dysfunc- reduction of fat mass during weight loss leads to the release tion are also possible consequences of chronic exposure to of POPs from adipocytes into the circulation (19). As the low-dose POP mixtures (1,9,11). primary physiological function of insulin in adipose tissue In addition to strong lipophilic POPs with long half-lives, is the suppression of lipolysis, elevated lipolysis in people less lipophilic chemicals with brief half-lives, such as poly- with insulin resistance can also enhance the release of POPs cyclic aromatic hydrocarbons, bisphenol A, synthetic musk from adipose tissue into the circulation with increased compounds, triclosan and nonylphenol, have been detected release of free fatty acids (20). However, weight gain can in adipose tissue (12,13). Therefore, adipose tissue can be decrease this effect by sequestering POPs from the circula- considered as an organ storing various exogenous tion into adipose tissue (21). An experimental animal study chemicals that are not easily metabolized and excreted clearly demonstrated that weight loss redistributed hexa- from the body. chlorobenzene (a POP) from adipose tissue to critical organs such as the brain and kidneys; however, weight gain reversed this effect (22). Hexachlorobenzene in the liver Adipose tissue is an important protective organ increased after weight cycling (i.e. weight regain following against persistent organic pollutants weight loss) (22). These findings suggest that changes in Once POPs enter the body, they are readily distributed weight affect the concentration of POPs in adipose tissue through the lymph and blood to their primary deposition and critical organs. site, adipocyte lipid droplets in adipose tissue, although we In fact, the two situations that cause the increased release note that the liver is another major storage site for certain of POPs from adipose tissue seem to be contradictory from types of POPs like dioxins, particularly at high doses the viewpoint of fat mass because weight loss makes people (5,14). Compared with other critical organs, adipose tissue less obese, while obesity is the most common cause of insu- is a relatively safe organ for POP accumulation because it lin resistance. Nevertheless, both situations increase the is a natural location for lipid storage. Therefore, the storage release of POPs from adipose tissue, although their patterns of POPs in adipose tissue can reduce their burden on other of release can differ. We suspect that the release of POPs due critical organs. Because the half-lives of POPs range from to obesity-related insulin resistance is more subtle and several months to years, storing POPs safely before they chronic than the release that occurs during weight loss. are finally eliminated is important to human health. The potential health effects of POPs during weight change Several animal experiments have demonstrated the possi- also contradict the conventional wisdom of weight change; ble protective effects of adipose tissue against POPs. For typically, weight loss is considered beneficial, whereas example, treatment with PCBs results in impaired glucose weight gain is considered harmful.

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It is important to emphasize that greater adipose tissue as following sections present three examples of puzzling the primary storage site for POPs can be more advantageous findings from the obesity literature and the role that POPs than less adipose tissue only if uncontrolled lipolysis does play in these findings. not develop. In addition, more subcutaneous adipose tissue is better than more visceral adipose tissue because the latter Three examples of puzzling findings from is a less stable storage site for POPs (23). It may be related to obesity research the higher lipolytic activity in visceral adipose tissue in com- parison with subcutaneous adipose tissue (24). This differ- The obesity paradox ence might partially explain why subcutaneous fat plays a protective role according to human and animal studies in Although obesity is an important risk factor for many chronic contrast with the detrimental effects of visceral adipose diseases, overweight and obese patients with these diseases tissue (25). show a better survival rate than patients with ideal body A recent human study reporting that the plasma levels of weights, suggesting that obesity has a protective effect (31). POPs were higher in the metabolically abnormal obese This phenomenon is called the ‘obesity paradox’. The obe- phenotype than in the metabolically healthy but obese phe- sity paradox is also observed among the elderly (32). The in- notype supports this hypothesis (26). One relevant finding accurate assessment of body fat using the conventional BMI, is that type 2 diabetes was rare among individuals with selective survival bias, better nutritional reservation and/or very low serum concentrations of POPs in the general US aggressive treatment among obese patients might explain population, even if these people were obese, which suggests this phenomenon (31). In contrast to the current paradigm the possibility that POPs play a more critical role than ad- of obesity, however, adipose tissue is likely the first line of ipose tissue in the pathogenesis of type 2 diabetes (27,28). defence, and it protects critical organs from the possible Therefore, the efficacy of adipose tissue as a stable harmful effects of POPs as stated previously. If this specific storage site for lipophilic chemicals such as POPs may be role of adipose tissue becomes more significant among pa- a crucial factor that determines metabolic health regardless tients with chronic diseases or the elderly, then the obesity of adiposity. paradox can be explained. A more fundamental possibility can be proposed. Under In general, chronic diseases and old age are considered to the current paradigm, chronic low-grade inflammation of be conditions featuring a disturbance of homeostasis that adipose tissue is a key mechanism of obesity-related dis- affects various cellular functions at the molecular level. eases; the enlarged adipocytes of obese individuals recruit The detrimental effects of POPs could be more serious pro-inflammatory cells and release a range of cytokines, among individuals with functionally impaired cells because which predispose toward insulin resistance through ectopic of homeostatic imbalance than those without chronic fat accumulation in non-adipose tissue (29,30). However, diseases or those who are younger. It is worth noting that the uncontrolled leakage of poorly biodegradable POPs glutathione depletion and mitochondrial dysfunction from enlarged or necrotic adipocytes of obese individuals (which are suspected to be possible molecular mechanisms to interstitial spaces between adipocytes can be an underly- linking chronic exposure to low-dose POP mixtures to ing cause of inflammatory changes in adipose tissue because many diseases (1,9,11)) are commonly found in a myriad of the presence of foreign bodies is an important cause of in- diseases and the elderly (33,34). In addition, patients with flammation. In fact, chronic treatment with low-dose POP chronic diseases or the elderly might not metabolize and elim- mixtures in mice led to a chronic state of low-grade inflam- inate POPs as efficiently as healthy or young people (35). mation in adipose tissue, including macrophage infiltration Therefore, the role that adipose tissue plays as a protective and up-regulation of pro-inflammatory cytokines (10). On organ might be more critical when the obesity paradox is the other hand, when weight loss happens, POPs in the in- observed. terstitial spaces of adipose tissue might be more easily Interestingly, one study reported that the association be- drained to blood and lymph, leading to the immediate tween fat mass and mortality among elderly people differed reduction of pro-inflammatory reaction in adipose tissue. depending on the serum concentrations of POPs (36). The In this scenario, POPs may explain even the possible health obesity paradox was clearly observed among elderly people effects from the viewpoint of fat mass. with high-serum POP concentrations but not those with Several conditions related to adiposity (obesity without relatively low-serum POP concentrations. For example, in insulin resistance, obesity with insulin resistance, weight elderly subjects that had high-serum POP concentrations, loss and weight gain) commonly occur in modern societies, the risk of mortality in subjects with high fat mass was only and many people experience some of these events more than one-fifth that of subjects with low fat mass. However, in el- once during their lifetime. Therefore, the toxicodynamics derly subjects that had low-serum POP concentrations, the and health-related effects of POPs are directly related to risk of mortality in subjects with high-fat mass was two to the health effects of obesity and weight change. The three times higher than that of subjects with low-fat mass.

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Compared with elderly people with low-serum POP concen- adipose tissue might have counteracted the improvements trations, those with high-serum POP concentrations already in the traditional cardiovascular risk factors observed ear- have a higher burden of POP metabolism and a higher lier during the study. The increase in serum POP concentra- chance that these chemicals would reach critical organs. Un- tions after weight loss is proportional to the magnitude of der this condition, a large and relatively safe reserve for weight loss (42). Therefore, to protect critical organs, it is storing POPs and other lipophilic chemicals can improve essential to increase the metabolism and elimination of survival. POPs based on the rate at which they are released from Although this observation (36) must be replicated, the adipose tissue. However, because the body’s capacity to different associations between obesity and mortality based metabolize POPs is limited, intensive weight loss might on serum levels of POPs might not always be observed in negatively affect various organs. other populations. If most people have concentrations of Importantly, the release of POPs into the circulation POPs above certain levels, then the protective role of obesity during weight loss can lead to repeated cycles of weight would be observed in all study subjects, even if participants gain/loss known as ‘the yo-yo phenomenon’ (22). In many are stratified based on POP levels. human studies, weight cycling has been associated with an increased risk of cardiovascular and total mortality (43). However, given that weight cycling is commonly the result The adverse effects of intensive intentional weight of intentional weight loss, which is considered a healthy loss behaviour, the validity of the epidemiological findings It is well known that weight loss intervention studies have concerning weight cycling has often been questioned (44). shown improvements in the cardiovascular risk profiles of However, POPs released from adipose tissue during inten- many obese people. However, if POPs are not eliminated sive weight loss might explain the findings regarding weight from the body, then the increased release of POPs from cycling in humans. adipose tissue into the circulation during weight loss can In fact, the pattern of weight loss of the intensive lifestyle lead to undesirable outcomes, especially in the long term. intervention group in the Look AHEAD study (40) was Despite the immediate release of POPs from adipose tissue consistent with inadequate excretion of POPs and weight during weight loss and possible negative effects on resting cycling. For example, the intervention group experienced a metabolic rate, thyroid hormone levels and liver function mean weight loss of 8.6% after 1 year, weight regain during tests (37–39), the net effect of weight loss in the short term years 2–5 and then gradual weight loss over the last 5 years would be revealed as favourable because of the significant of the follow-up period. Compared with the intervention benefits of decreased fat mass. However, the early beneficial group, the mean weight loss in the control group at the net effect of weight loss can be reversed over time, especially 1-year follow-up assessment was only 0.7%; however, the when the POPs released from adipose tissue are not weight loss occurred gradually and without weight regain. efficiently eliminated from the body. At the end of the study, the weight loss was 6.0% in the in- Findings in a recent large randomized controlled study of tervention group and 3.5% in the control group. Therefore, overweight or obese patients with type 2 diabetes (the Look although the absolute weight loss was lower, the pattern of AHEAD study) (40) are consistent with this speculation. weight loss in the control group was less harmful than that This study evaluated the effects of an intensive lifestyle in the intervention group with regard to POPs. This finding intervention focusing on weight loss on the development might explain why the rate of cardiovascular events was of cardiovascular disease over 10 years. As expected, signif- similar between the two groups despite the remarkable icant weight loss and improvements in traditional cardio- improvements in traditional cardiovascular risk factors vascular risk factors were observed, especially during an observed in the intervention group. earlier follow-up period. However, no difference was found POPs-related problems due to weight loss are more seri- in the rate of cardiovascular events between the intensive ous in older adults than in younger adults. First, adipose tis- lifestyle intervention group and control group at the 10-year sue is more contaminated with POPs and other chemicals in follow-up assessment. the elderly than in younger people because chemicals such The authors stated that this finding was unexpected. as POPs that are poorly metabolized tend to accrue with Several possible explanations were suggested with regard age (45). Therefore, more POPs are released from adipose to the methodology, including the use of lower doses of tissue into the circulation when elderly people lose body cardioprotective drugs in the intervention group, the char- weight than when younger people lose the same amount acteristics of the participants (i.e. whether they belonged of weight. Second, the physiological ability to metabolize to a subgroup that was healthier than the general popula- and excrete xenobiotics decreases with age (35). We pre- tion with type 2 diabetes or an unhealthier subgroup) and sume that the amount of POPs released from adipose tissue an insufficient follow-up period (40,41). However, we point into the circulation and the likelihood that these chemicals out that the delayed adverse effects of POPs released from will reach critical organs are higher among the elderly than

younger people. Therefore, the net benefits of weight loss In fact, even the positive association between midlife obe- decrease with age, and the health benefits of weight loss sity and dementia may be explained by the release of OCPs among the elderly are unclear even if it is intentional. from adipose tissue due to obesity-related insulin resistance rather than adiposity itself. The protective role that midlife obesity plays with regard to the risk of dementia, which Obesity and dementia was observed in the recent large cohort study (54), supports this speculation. Unless OCPs are significantly released into One of the most puzzling findings regarding obesity has the bloodstream through insulin resistance, even midlife been observed with regard to dementia. Conventionally, obesity may not be a risk factor for dementia. Figure 1 pre- obesity is linked to dementia as a direct effect of adiposity sents four scenarios that demonstrate how midlife obesity or through obesity-related disorders such as type 2 diabetes and weight change after midlife can lead to a positive asso- and hypertension (46). However, findings are conflicting ciation with midlife obesity but an inverse association with with regard to the possible links between obesity in middle late life obesity regarding the risk of dementia. age and older age individuals and the subsequent develop- Relatedly, a 25-year longitudinal study (55) showed that ment of dementia. In a review of epidemiological studies mortality was highest among men who were previously from 2003 to 2013 (47), midlife obesity was positively asso- overweight and lost weight later in life (scenario 2). This ciated with the risk of dementia, whereas obesity later in life rate was higher than the risk of mortality in consistently decreased the risk of dementia. In a recent large cohort overweight men (scenario 1). In contrast, weight gain after study of nearly 2 million people (48), however, both midlife middle age (scenario 4) showed no notable effect on the risk and late-life body mass index were inversely related to the of mortality compared with the risk among people who had incidence of dementia, suggesting that obesity during a normal body weight throughout their lives (scenario 3). midlife is also protective. Again, several methodological is- Importantly, unintentional weight loss is commonly sues were suggested to explain these diverse findings (49). observed before the diagnosis of dementia (56), and it One important finding that dementia researchers have predicts the progression from mild cognitive impairment to overlooked is that serum concentrations of OCPs, a class dementia (57). This is currently interpreted to be caused by of POPs, were recently linked to the risk of dementia and a declining ability for self-care or appetite loss, which usually cognitive impairment in the general population (50–52). co-exists with the subclinical progressive loss of cognitive Although high doses of OCPs are well known to act as function, rather than a risk factor that contributes to the neurotoxins (53), these findings were surprising because development of dementia (46). However, weight loss can their current human body burden is very low after their directly increase the risk of dementia by releasing OCPs into production and use was banned during the 1970s and the bloodstream. In fact, unintentional weight loss is com- 1980s. Therefore, the recent link between OCPs and mon among patients with various chronic diseases, although dementia suggests that chronic exposure to low doses of it is simply regarded as a marker of poor prognosis. OCPs can be much more harmful to neuronal function than However, regardless of the cause of the weight loss in researchers previously thought. Indeed, the current elderly patients, the release of POPs through unintentional weight population is the first generation to have been exposed to loss can worsen their prognosis. Proper nutritional interven- these chemicals throughout their lifetimes. tions to prevent unintentional weight loss among patients Serum concentrations of OCPs are highly correlated with are required. brain concentrations of OCPs because of the direct transport of OCPs across the blood–brain barrier (52). Accord- Possible interventions to increase the ingly, the toxicodynamics of OCPs in relation to adiposity elimination of POPs and weight change may also explain the confusing results regarding the relationship between obesity and dementia. Notwithstanding the release of POPs from adipose tissue to For example, body weight among the elderly is determined the circulation during weight loss or insulin resistance, their by body weight during middle age and the subsequent harmful effects can be minimized if they are more efficiently changes that occur before late life. Groups of obese elderly eliminated from the body. Although a variety of chemicals might include more individuals who have experienced are excreted through urine, lipophilic chemicals including weight gain than groups of lean elderly, whereas the reverse POPs are primarily excreted in faeces through bile; however, might be true regarding weight loss. Therefore, with regard transluminal passive diffusion has also been reported with to OCPs, a history of weight change may create more regard to certain POPs (5,58). The reabsorption of excreted favourable conditions for the brains of the obese elderly, POPs through enterohepatic recirculation is one mechanism an advantage not experienced by the lean elderly. These that can increase the half-lives of POPs (59). Despite limited situations suggest that late-life obesity protects against the direct evidence in humans, several interventions to facilitate risk of dementia. the excretion of POPs in faeces can be suggested.

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Figure 1 Four hypothetical scenarios regarding the relationship between obesity and dementia in terms of persistent organic pollutants (POPs). An obese group in middle age (risk score: ‘+’) might have a higher risk of dementia than a lean group (risk score: ‘0’) due to the release of POPs through insulin resistance. However, this association differs in the elderly because the body weights of these individuals are determined by their body weights in middle age and the subsequent changes that occur up to late life. Weight loss (risk score: ‘+’) increases the release of POPs from adipose tissue to the circulation; however, weight gain (risk score: ‘À’) decreases this release. A risk score of ‘0’ is assigned to people with no weight change. Therefore, the risk score for the elderly is the sum of the risk score during middle life and the risk score throughout the weight change. As a result, the mean risk score for two obese elderly individuals is ‘0’ (i.e. the mean of ‘+’ and ‘À’), whereas the mean risk score for two lean elderly individuals is ‘+’ (i.e. the mean of ‘++’ and ‘0’). There- fore, the positive association between midlife obesity and dementia can change into an inverse association between late-life obesity and dementia.

First, bile formation and secretion from hepatocytes is the Exercise is another efficient intervention. Chronic physical first step to eliminate POPs from the body. Most of the activity substantially increased the hepatobiliary clearance major transporters and enzymes that determine the mecha- of endogenous and exogenous chemicals according to nisms of bile formation and secretion in hepatocytes have animal experiments (69,70). been characterized at the molecular level, offering the Third, Dr Jandacek’s research group suggested blocking opportunity to regulate this process therapeutically (60). the enterohepatic recirculation of POPs as a possible inter- Phytochemicals in some herb or plant food have been vention (59). Dietary fibre, nonabsorbable lipids such as reported to increase bile secretion through the synthesis of olestra or bile acid resins such as cholestyramine reportedly bile salts, changes in transporter expression/activity and have the ability to absorb POPs in the bile and increase their the evocation of signalling pathways (61–64). A diet rich excretion in faeces (22,71–75). With the exception of in phospholipids can also increase bile formation and bile dietary fibre, however, other strategies (e.g. olestra and acid transport (65). cholestyramine) can increase the risk of fat-soluble vitamin Second, bile flow in the intrahepatic and extrahepatic deficiencies (76,77). Although this potentially adverse effect biliary tracts should not be stagnant. Bile stasis for any rea- can be offset by vitamin supplementation, their long-term son hinders the excretion of POPs from the liver to the use might not be desirable. Among the various dietary intestine. The most common reasons for this phenomenon fibres, the binding effects of whole grains seemed to be the are gallstone or biliary sludge. Symptomatic gallstones are most effective because of their high content of lignins (72). generally removed, and medications such as In contrast to common dietary fibres consisting of polysac- ursodeoxychloic acid are used for patients with serious bile charides, lignins are relatively hydrophobic and aromatic stasis (66). However, chronic mild cholestasis without any organic polymers, which are important for binding symptoms or signs can still disturb the excretion of POPs. lipophilic xenobiotics such as POPs (78). However, a Some health behaviour-based approaches have been prerequisite for the successful enterohepatic recirculation reported to increase bile flow. For example, time-restricted intervention is the efficient excretion of bile to the intestine. feeding with intermittent fasting was reported to increase If POPs cannot properly reach the small intestine for any bile flow (67) because the distinct cycle of gallbladder fill- reason, then the intervention at the site of enterohepatic ing and emptying is important to control bile flow (68). recirculation might not be effective.

The dilemma is that POPs can directly impair bile secre- behaviours to decrease the body burden of POPs can be tion from hepatocytes (79) and induce cholestasis (80). adopted as the healthiest method of weight loss for obese Therefore, although the elimination of POPs can be persons. One difference is that although fish is generally increased using some of the interventions described previ- recommended as a healthy food as the best source of ously, the excessive burden of POPs on the liver still remains omega-3 fatty acids, it is also a significant source of POPs problematic. Actually, both obesity and rapid weight loss (83). The recent contradictory epidemiological findings among obese people increase the risk of cholestasis and concerning the health effects of fish consumption can also gallstone disease (81). These contradictory findings might be explained by the mixed effects of the beneficial nutrients also be explained by the release of POPs from adipose tissue and harmful chemicals contained in fish (84,85). through obesity-related insulin resistance or weight loss. Importantly, in addition to POPs, a wide range of pharma- Obesity-inducing effects of chemicals cological drugs, especially highly lipophilic drugs, can (obesogens) induce cholestasis (82). These complications should be taken into consideration when planning long-term pharma- The rise in global obesity rates over the last several decades cological interventions. has been substantial and widespread (86). The aetiology of Regarding health behaviours, time-restricted feeding the obesity epidemic has been hotly debated (87), but the combined with intermittent fasting, exercise and a diet common belief is that changes in body weight and adiposity enriched with whole grains and phytochemicals are impor- are the results of chronic positive energy balance, meaning tant to increase the elimination of POPs. Avoiding POP- that energy expenditure is less than energy intake. However, contaminated animal fat, including fish, is another obesity-inducing effects of many EDCs have recently important dietary habit that can reduce the amount of POPs become an important piece of the obesity epidemic that enter the body from the environment, especially when a puzzle (88). substantial amount of POPs are already released from Exposure to obesogenic chemicals can predispose animals adipose tissue to the circulation. Interestingly, all these to accumulate more fat, and these effects can be transmitted behaviours that decrease the body burden of POPs are very to their descendants (89). Obesogens typically act at similar to well-accepted health-promoting behaviours. As low, environmentally relevant doses (often below the they seem to be effective for weight loss as well, the health no-observed-adverse-effect level) during critical windows

Figure 2 The relationship between adipose tissue and persistent organic pollutants (POPs). When people are exposed to the same amount of POPs, people with more adipose tissue have an advantage over those with less adipose tissue because the former have a more sufficient and safe reservoir to store harmful chemicals in the absence of insulin resistance (scenario 1: S1). However, when insulin resistance develops (scenario 2: S2) and weight loss occurs (scenario 3: S3), the release of POPs from adipose tissue into the circulation increases, which increases the risk that POPs will reach critical organs. How- ever, weight gain reduces this possibility (scenario 4: S4). The viewpoint of fat mass may also be explained by POPs because the release of POPs from enlarged or necrotic adipocytes to interstitial spaces can induce pro-inflammatory reactions in adipose tissue and related pathological changes in other organs.

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of prenatal or postnatal development to promote obesity Currently, most of the studies on obesity and weight later in life (89). Different obesogenic compounds may have change do not consider the role of POPs. Because chronic different mechanisms of action, some of which might exposure to low levels of POPs has emerged as a risk factor affect the number and size of fat cells or the hormones of many diseases of the endocrine, immune, nervous and that affect appetite, satiety, food preferences and energy reproductive systems, future epidemiological and experi- metabolism (90). mental studies should consider that, in modern societies, In addition to compounds classified as POPs, several dozen the adipose tissues of both humans and experimental ani- EDCs have now been shown to cause weight gain (90). For mals are widely contaminated with POPs. Gut microbiome example, plasticizers and plastics, organophosphate pesti- composition, the latest research topic linked to obesity and cides, fungicides, flame retardants, and smoking and nico- obesity-related diseases (93), can be also influenced by the tine have all been linked to obesity in animals (90). presence of various xenobiotics like POPs in faeces (94–96). Certainly, however, this figure could be just the tip of the ice- Although specific designs differ depending on the purpose berg as there are close to 800 chemicals known or suspected of the study, POPs should be measured in future studies that to be capable of acting as EDCs (91). Moreover, only a small evaluate the health effects of obesity and weight change. If portion of the more than 85,000 chemicals included in the the measurement of POPs is impossible for practical US Toxic Substances Control Act inventory have been eval- reasons, then POPs should at least be considered in the in- uated for potential EDC activity (92). terpretations of the findings. Well-designed human interven- However, the obesity-inducing effects of chemicals need tions seeking to increase the elimination of POPs should to be re-evaluated from the viewpoint of the protective role have a high priority in future research even though it can of adipose tissue against POPs and other lipophilic be technically difficult to measure the elimination of POPs. chemicals. This can represent adaptation of living organ- Even though faeces are the main POPs excretion route, isms to secure a relatively safe reservoir for lipophilic POPs in faeces may not be accurately measured because chemicals such as POPs. Although the chemicals acting as they would not be homogenously distributed across the obesogens can be detrimental to health through a variety total mass of faeces and only a small part of faeces can be of other pathways, their obesogenic effects themselves, practically collected for the measurement of POPs in human especially the adipogenesis-promoting effect, might not be studies. as harmful as researchers are currently speculating. On the One troublesome issue is that POPs, in addition to con- contrary, chemicals that suppress adipogenesis might be taminating the food consumed by humans, have contami- more harmful than obesogens as they may diminish the nated laboratory animal diets (97). The fact that these diets safe storage site for unavoidable lipophilic chemicals in are polluted with low-dose POPs and other toxic environ- chemical-contaminated modern societies. mental chemicals has enormous consequences for current practices in biomedical research (97). Finally, if weight loss is planned for any reason, then the magnitude and rate of Conclusions weight loss should be adjusted and the interventions to increase the elimination of POPs should be considered to min- Realistically, the toxicodynamics of POPs cannot be sepa- imize the potential health hazards caused by their release. rated from the dynamics of adipose tissue. Additionally, the possible health effects of obesity and weight change differ with respect to fat mass and POPs. In the context of fat Conflicts of interest statement mass, obesity, especially with insulin resistance, and weight No conflict of interest statement. gain are found to be harmful. However, in the context of POPs, obesity with insulin resistance and weight loss are found to be harmful, but obesity without insulin resistance Acknowledgements and weight gain could be beneficial; most effects of POPs This study was supported by the Korean Health Technology are opposite to those commonly expected in obesity. These R&D Project (HI13C0715), funded by the Ministry of observations may help to explain the puzzling findings Health and Welfare; and the Environmental Health Action obtained from epidemiological studies considering only Program (2016001370002), funded by the Korea Ministry adiposity-related factors. Figure 2 summarizes how POPs, of Environment of the Republic of Korea. adiposity and weight change interact with each other. Im- portantly, POPs may explain the possible health effects even from the viewpoint of fat mass through pro-inflammatory References changes in adipose tissue, which would be related to the 1. Lee DH, Porta M, Jacobs DR Jr, Vandenberg LN. Chlorinated release of POPs from enlarged or necrotic adipocytes to persistent organic pollutants, obesity, and type 2 diabetes. Endocr interstitial spaces. Rev 2014; 35: 557–601.

2. Verner MA, Sonneborn D, Lancz K et al. Toxicokinetic model- 20. Irigaray P, Newby JA, Lacomme S, Belpomme D. Overweight/ ing of persistent organic pollutant levels in blood from birth to obesity and cancer genesis: more than a biological link. Biomed 45 months of age in longitudinal birth cohort studies. Environ Pharmacother 2007; 61: 665–678. Health Perspect 2013; 121: 131–137. 21. Lim JS, Son HK, Park SK, Jacobs DR Jr, Lee DH. Inverse 3. Kim KS, Lee YM, Kim SG et al. Associations of organochlorine associations between long-term weight change and serum concen- pesticides and polychlorinated biphenyls in visceral vs. subcutane- trations of persistent organic pollutants. Int J Obes (Lond) 2011; ous adipose tissue with type 2 diabetes and insulin resistance. 35: 744–747. Chemosphere 2014; 94: 151–157. 22. Jandacek RJ, Anderson N, Liu M, Zheng S, Yang Q, Tso P. 4. Malarvannan G, Dirinck E, Dirtu AC et al. Distribution of Effects of yo-yo diet, caloric restriction, and olestra on tissue distri- persistent organic pollutants in two different fat compartments bution of hexachlorobenzene. Am J Physiol Gastrointest Liver from obese individuals. Environ Int 2013; 55:33–42. Physiol 2005; 288: G292–G299. 5. Birnbaum LS. The role of structure in the disposition of 23. Dirinck E, Dirtu AC, Jorens PG, Malarvannan G, Covaci A, halogenated aromatic xenobiotics. Environ Health Perspect 1985; Van Gaal LF. Pivotal role for the visceral fat compartment in the 61:11–20. release of persistent organic pollutants during weight loss. J Clin 6. Carpenter DO. Effects of Persistent and Bioactive Organic Endocrinol Metab 2015; 100: 4463–4471. Pollutants on Human Health. Wiley: Hoboken, New Jersey, 2013. 24. Wajchenberg BL. Subcutaneous and visceral adipose tissue: 7. Ruzzin J, Lee DH, Carpenter DO, Jacobs DR Jr. Reconsidering their relation to the metabolic syndrome. Endocr Rev 2000; 21: metabolic diseases: the impacts of persistent organic pollutants. 697–738. Atherosclerosis 2012; 224:1–3. 25. Despres JP. Body fat distribution and risk of cardiovascular 8. Van den Berg M, De Jongh J, Poiger H, Olson JR. The disease: an update. Circulation 2012; 126: 1301–1313. toxicokinetics and metabolism of polychlorinated dibenzo- 26. Gauthier MS, Rabasa-Lhoret R, Prud’homme D et al. The met- p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance abolically healthy but obese phenotype is associated with lower for toxicity. Crit Rev Toxicol 1994; 24:1–74. plasma levels of persistent organic pollutants as compared to the 9. Ruzzin J, Petersen R, Meugnier E et al. Persistent organic metabolically abnormal obese phenotype. J Clin Endocrinol Metab pollutant exposure leads to insulin resistance syndrome. Environ 2014; 99: E1061–E1066. Health Perspect 2010; 118: 465–471. 27. Lee DH, Lee IK, Song K, Steffes M et al. A strong dose– 10. Ibrahim MM, Fjaere E, Lock EJ et al. Chronic consumption response relation between serum concentrations of persistent of farmed salmon containing persistent organic pollutants causes organic pollutants and diabetes: results from the National Health insulin resistance and obesity in mice. PLoS One 2011; 6: and Examination Survey 1999–2002. Diabetes Care 2006; 29: e25170. 1638–1644. 11. Lim S, Cho YM, Park KS, Lee HK. Persistent organic 28. Porta M. Persistent organic pollutants and the burden of pollutants, mitochondrial dysfunction, and metabolic syndrome. diabetes. Lancet 2006; 368: 558–559. Ann N Y Acad Sci 2010; 1201: 166–176. 29. Sell H, Habich C, Eckel J. Adaptive immunity in obesity and 12. Moon HB, Lee DH, Lee YS, Kannan K. Occurrence and insulin resistance. Nat Rev Endocrinol 2012; 8: 709–716. accumulation patterns of polycyclic aromatic hydrocarbons and 30. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, synthetic musk compounds in adipose tissues of Korean females. and cardiometabolic disease. N Engl J Med 2014; 371: Chemosphere 2012; 86: 485–490. 1131–1141. 13. Geens T, Neels H, Covaci A. Distribution of bisphenol-A, 31. Antonopoulos AS, Oikonomou EK, Antoniades C, Tousoulis triclosan and n-nonylphenol in human adipose tissue, liver and D. From the BMI paradox to the obesity paradox: the obesity– brain. Chemosphere 2012; 87: 796–802. mortality association in coronary heart disease. Obes Rev 2016; 14. Emond C, Birnbaum LS, DeVito MJ. Use of a physiologi- 17: 989–1000. cally based pharmacokinetic model for rats to study the 32. Oreopoulos A, Kalantar-Zadeh K, Sharma AM, Fonarow GC. influence of body fat mass and induction of CYP1A2 on the The obesity paradox in the elderly: potential mechanisms and pharmacokinetics of TCDD. Environ Health Perspect 2006; clinical implications. Clin Geriatr Med 2009; 25: 643–659, viii. 114: 1394–1400. 33. Nunnari J, Suomalainen A. Mitochondria: in sickness and in 15. Baker NA, Karounos M, English V et al. Coplanar health. Cell 2012; 148: 1145–1159. polychlorinated biphenyls impair glucose homeostasis in lean 34. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione C57BL/6 mice and mitigate beneficial effects of weight loss on metabolism and its implications for health. J Nutr 2004; 134: glucose homeostasis in obese mice. Environ Health Perspect 2013; 489–492. 121: 105–110. 35. McLachlan AJ, Pont LG. Drug metabolism in older people – a 16. Tuomisto JT, Pohjanvirta R, Unkila M, Tuomisto J. TCDD- key consideration in achieving optimal outcomes with medicines. J induced anorexia and wasting syndrome in rats: effects of diet- Gerontol A Biol Sci Med Sci 2012; 67: 175–180. induced obesity and nutrition. Pharmacol Biochem Behav 1999; 36. Hong NS, Kim KS, Lee IK et al. The association between obe- 62: 735–742. sity and mortality in the elderly differs by serum concentrations of 17. La Merrill M, Emond C, Kim MJ et al. Toxicological function persistent organic pollutants: a possible explanation for the obesity of adipose tissue: focus on persistent organic pollutants. Environ paradox. Int J Obes (Lond) 2012; 36: 1170–1175. Health Perspect 2013; 121: 162–169. 37. Pelletier C, Doucet E, Imbeault P, Tremblay A. Associations 18. Needham LL, Burse VW, Head SL et al. Adipose tissue/serum between weight loss-induced changes in plasma organochlorine partitioning of chlorinated hydrocarbon pesticides in humans. concentrations, serum T(3) concentration, and resting metabolic Chemosphere 1990; 20: 975–980. rate. Toxicol Sci 2002; 67:46–51. 19. Imbeault P, Tremblay A, Simoneau JA, Joanisse DR. Weight 38. Kim MJ, Marchand P, Henegar C et al. Fate and complex loss-induced rise in plasma pollutant is associated with reduced pathogenic effects of dioxins and polychlorinated biphenyls in skeletal muscle oxidative capacity. Am J Physiol Endocrinol Metab obese subjects before and after drastic weight loss. Environ Health 2002; 282: E574–E579. Perspect 2011; 119: 377–383.

© 2016 The Authors. Obesity Reviews published by John Wiley & Sons Ltd Obesity Reviews on behalf of World Obesity Federation 10 Obesity and persistent organic pollutants Y.-M. Lee et al. obesity reviews

39. Tremblay A, Pelletier C, Doucet E, Imbeault P. Thermogenesis 61. Crocenzi FA, Roma MG. Silymarin as a new hepatoprotective and weight loss in obese individuals: a primary association with or- agent in experimental cholestasis: new possibilities for an ancient ganochlorine pollution. Int J Obes Relat Metab Disord 2004; 28: medication. Curr Med Chem 2006; 13: 1055–1074. 936–939. 62. Yang D, Yang J, Shi D, Deng R, Yan B. Scoparone potentiates 40. Wing RR, Bolin P, Brancati FL et al. Cardiovascular effects of transactivation of the bile salt export pump gene and this effect is intensive lifestyle intervention in type 2 diabetes. N Engl J Med enhanced by cytochrome P450 metabolism but abolished by a 2013; 369: 145–154. PKC inhibitor. Br J Pharmacol 2011; 164: 1547–1557. 41. Gerstein HC. Do lifestyle changes reduce serious outcomes in 63. Accatino L, Pizarro M, Solis N, Koenig CS. Effects of diabetes? N Engl J Med 2013; 369: 189–190. diosgenin, a plant-derived steroid, on bile secretion and hepatocel- 42. Hue O, Marcotte J, Berrigan F et al. Increased plasma levels of lular cholestasis induced by estrogens in the rat. Hepatology toxic pollutants accompanying weight loss induced by hypocaloric 1998; 28: 129–140. diet or by bariatric surgery. Obes Surg 2006; 16: 1145–1154. 64. Ofem O, Ikpi D, Antai A. Altered biliary flow rate and bile 43. Muls E, Kempen K, Vansant G, Saris W. Is weight cycling det- composition following consumption of ethanolic fruit extract of rimental to health? A review of the literature in humans. Int J Obes Dennettia in rats. Int J Appl Basic Med Res 2014; 4:20–24. Relat Metab Disord 1995; 19(Suppl 3): S46–S50. 65. Rioux F, Perea A, Yousef IM et al. Short-term feeding of a diet 44. Jeffery RW. Does weight cycling present a health risk? Am J enriched in phospholipids increases bile formation and the bile acid Clin Nutr 1996; 63: 452S–455S. transport maximum in rats. Biochim Biophys Acta 1994; 1214: 45. Hue O, Marcotte J, Berrigan F et al. Plasma concentration of 193–202. organochlorine compounds is associated with age and not obesity. 66. Qureshi WA. Intrahepatic cholestatic syndromes: pathogene- Chemosphere 2007; 67: 1463–1467. sis, clinical features and management. Dig Dis 1999; 17:49–59. 46. Kiliaan AJ, Arnoldussen IA, Gustafson DR. Adipokines: a link 67. Hatori M, Vollmers C, Zarrinpar A et al. Time-restricted between obesity and dementia? Lancet Neurol 2014; 13: 913–923. feeding without reducing caloric intake prevents metabolic diseases 47. Emmerzaal TL, Kiliaan AJ, Gustafson DR. 2003–2013: a de- in mice fed a high-fat diet. Cell Metab 2012; 15: 848–860. cade of body mass index, Alzheimer’s disease, and dementia. J 68. Housset C, Chretien Y, Debray D, Chignard N. Functions of Alzheimers Dis 2015; 43: 739–755. the gallbladder. Compr Physiol 2016; 6: 1549–1577. 48. Qizilbash N, Gregson J, Johnson ME et al. BMI and risk of de- 69. Watkins JB 3rd, Crawford ST, Sanders RA. Chronic voluntary mentia in two million people over two decades: a retrospective exercise may alter hepatobiliary clearance of endogenous and exog- cohort study. Lancet Diabetes Endocrinol 2015; 3: 431–436. enous chemicals in rats. Drug Metab Dispos 1994; 22: 537–543. 49. Gustafson D. BMI and dementia: feast or famine for the brain? 70. Yiamouyiannis CA, Martin BJ, Watkins JB 3rd. Chronic Lancet Diabetes Endocrinol 2015; 3: 397–398. physical activity alters hepatobiliary excretory function in rats. J 50. Kim KS, Lee YM, Lee HW, Jacobs DR Jr, Lee DH. Associa- Pharmacol Exp Ther 1993; 265: 321–327. tions between organochlorine pesticides and cognition in U.S. 71. Aozasa O, Ohta S, Nakao T, Miyata H, Nomura T. Enhance- elders: National Health and Nutrition Examination Survey 1999– ment in fecal excretion of dioxin isomer in mice by several dietary 2002. Environ Int 2015; 75:87–92. fibers. Chemosphere 2001; 45: 195–200. 51. Lee DH, Lind PM, Jacobs DR Jr, Salihovic S, van Bavel B, Lind 72. Sera N, Morita K, Nagasoe M, Tokieda H, Kitaura T, Tokiwa L. Association between background exposure to organochlorine H. Binding effect of polychlorinated compounds and environmental pesticides and the risk of cognitive impairment: a prospective study carcinogens on rice bran fiber. J Nutr Biochem 2005; 16:50–58. that accounts for weight change. Environ Int 2016; 89-90: 73. Jandacek RJ, Heubi JE, Buckley DD et al. Reduction of the 179–184. body burden of PCBs and DDE by dietary intervention in a 52. Richardson JR, Roy A, Shalat SL et al. Elevated serum pesti- randomized trial. J Nutr Biochem 2014; 25: 483–488. cide levels and risk for Alzheimer disease. JAMA Neurol 2014; 74. Sakurai K, Fukata H, Todaka E, Saito Y, Bujo H, Mori C. 71: 284–290. Colestimide reduces blood polychlorinated biphenyl (PCB) levels. 53. Colosio C, Tiramani M, Maroni M. Neurobehavioral effects Intern Med 2006; 45: 327–328. of pesticides: state of the art. Neurotoxicology 2003; 24: 577–591. 75. Arguin H, Sanchez M, Bray GA et al. Impact of adopting a 54. Qizilbash N, Gregson J, Johnson ME et al. BMI and risk of de- vegan diet or an olestra supplementation on plasma organochlorine mentia in two million people over two decades: a retrospective concentrations: results from two pilot studies. Br J Nutr 2010; 103: cohort study. Lancet Diabetes Endocrinol 2015; 3: 431–436. 1433–1441. 55. Strandberg TE, Strandberg AY, Salomaa VV et al. Explaining 76. Thomson AB, Hunt RH, Zorich NL. Review article: olestra the obesity paradox: cardiovascular risk, weight change, and mor- and its gastrointestinal safety. Aliment Pharmacol Ther 1998; 12: tality during long-term follow-up in men. Eur Heart J 2009; 30: 1185–1200. 1720–1727. 77. Vroonhof K, van Rijn HJ, van Hattum J. Vitamin K deficiency 56. Sergi G, De Rui M, Coin A, Inelmen EM, Manzato E. Weight and bleeding after long-term use of cholestyramine. Neth J Med loss and Alzheimer’s disease: temporal and aetiologic connections. 2003; 61:19–21. Proc Nutr Soc 2013; 72: 160–165. 78. Ta CA, Zee JA, Desrosiers T et al. Binding capacity of various 57. Cova I, Clerici F, Rossi A et al. Weight loss predicts progression fibre to pesticide residues under simulated gastrointestinal of mild cognitive impairment to Alzheimer’s disease. PLoS One conditions. Food Chem Toxicol 1999; 37: 1147–1151. 2016; 11: e0151710. 79. Bucher S, Le Vee M, Jouan E, Fardel O. Regulation of hepatic 58. Macdonald TL. Chemical mechanisms of halocarbon metabo- drug transporter activity and expression by organochlorine pesti- lism. Crit Rev Toxicol 1983; 11:85–120. cides. J Biochem Mol Toxicol 2014; 28:119–128. 59. Jandacek RJ, Tso P. Enterohepatic circulation of organochlo- 80. Ayas Z, Ekmekci G, Ozmen M, Yerli SV. Histopathological rine compounds: a site for nutritional intervention. J Nutr changes in the livers and kidneys of fish in Sariyar Reservoir, Biochem 2007; 18: 163–167. Turkey. Environ Toxicol Pharmacol 2007; 23: 242–249. 60. Boyer JL. Bile formation and secretion. Compr Physiol 2013; 81. Everhart JE. Contributions of obesity and weight loss to 3: 1035–1078. gallstone disease. Ann Intern Med 1993; 119: 1029–1035.

82. Bhamidimarri KR, Schiff E. Drug-induced cholestasis. Clin 90. Heindel JJ, Newbold R, Schug TT. Endocrine disruptors and Liver Dis 2013; 17: 519–531, vii. obesity. Nat Rev Endocrinol 2015; 11: 653–661. 83. Letcher RJ, Bustnes JO, Dietz R et al. Exposure and effects 91. UNEP/WHO. State of the science of endocrine disrupting assessment of persistent organohalogen contaminants in arctic chemicals 2012. 2013. wildlife and fish. Sci Total Environ 2010; 408: 2995–3043. 92. US Environmental Protection Agency. Toxic Substance Con- 84. Jacobs DR Jr, Ruzzin J, Lee DH. Environmental pollutants: trol Act (TSCA) Chemical Substance Inventory. https://www.epa. downgrading the fish food stock affects chronic disease risk. J gov/tsca-inventory (accessed14 October 2016). Intern Med 2014; 276: 240–242. 93. Zhao L. The gut microbiota and obesity: from correlation to 85. Lee DH, Jacobs DR Jr. Inconsistent epidemiological findings on causality. Nat Rev Microbiol 2013; 11: 639–647. fish consumption may be indirect evidence of harmful contaminants 94. Lee HS, Lee JC, Lee IK et al. Associations among organochlo- in fish. J Epidemiol Community Health 2010; 64: 190–192. rine pesticides, Methanobacteriales, and obesity in Korean women. 86. Ng M, Fleming T, Robinson M et al. Global, regional, and PLoS One 2011; 6: e27773. national prevalence of overweight and obesity in children and 95. Zhang L, Nichols RG, Correll J et al. Persistent organic adults during 1980–2013: a systematic analysis for the Global pollutants modify gut microbiota-host metabolic homeostasis in Burden of Disease Study 2013. Lancet 2014; 384: 766–781. mice through aryl hydrocarbon receptor activation. Environ Health 87. Lavie CJ, McAuley PA, Church TS, Milani RV, Blair SN. Perspect 2015; 123: 679–688. Obesity and cardiovascular diseases: implications regarding fitness, 96. Choi JJ, Eum SY, Rampersaud E, Daunert S, Abreu MT, fatness, and severity in the obesity paradox. J Am Coll Cardiol Toborek M. Exercise attenuates PCB-induced changes in the 2014; 63: 1345–1354. mouse gut microbiome. Environ Health Perspect 2013; 121: 88. Chamorro-Garcia R, Blumberg B. Transgenerational effects of 725–730. obesogens and the obesity epidemic. Curr Opin Pharmacol 2014; 97. Mesnage R, Defarge N, Rocque LM, Spiroux de Vendomois J, 19: 153–158. Seralini GE. Laboratory rodent diets contain toxic levels of environ- 89. Janesick AS, Shioda T, Blumberg B. Transgenerational inheri- mental contaminants: implications for regulatory tests. PLoS One tance of prenatal obesogen exposure. Mol Cell Endocrinol 2014; 2015; 10: e0128429. 398:31–35.