Nov 7, 2017 - related compounds; endrin; mirex; heptachlor; ..... target genes such as CYPs, aldehyde dehydrogenase 3. (ALDH3), AhR repressor (AhRR), ...
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Persistent Organic Pollutants, Mitochondrial Dysfunction, and Metabolic Syndrome Hong Kyu Lee1 and Youngmi Kim Pak2 Department of Internal Medicine, College of Medicine, Eulji University, Seoul, South Korea Department of Physiology, College of Medicine, Kyung Hee University, Seoul, South Korea
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CHAPTER MENU
44.1 Introduction
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44.1 Introduction, 691 44.2 Health Hazard of Environmental Chemicals: A Short History, 691 44.3 Low‐Level Exposure to Multiple Chemicals, 692 44.4 POPs and Obesity Paradox, 692 44.5 Body Burden of Chemicals, 693 44.6 Diabetes Mellitus, Insulin Resistance, and Metabolic Syndrome, 693 44.7 Association of POPs with Diabetes and Metabolic Syndrome, 695 44.8 Toxic and Biological Effects of Some POPs via AhR, 696 44.9 Insulin Resistance and Mitochondrial Dysfunction, 698 44.10 Measurement of POPs, 702 44.11 Summary, 703 References, 703
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Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are worldwide public health problems. Currently, it is believed that high calorie diet and sedentary lifestyle are main causes of obesity and the interaction between genetic and environmental factors is associated in the onset of obesity, which are T2DM and MetS. However, 75–80% of obese people never develop T2DM (Gregg et al., 2007), so there may be other e nvironmental factors. Recent epidemiological studies suggest a possible contribution of environmental chemicals to metabolic diseases such as MetS, T2DM (Lee et al., 2006a), and insulin resistance (IR), a prediabetic state (Lee et al., 2007a). More importantly, mitochondrial dysfunction was suggested to be an underlying cause of IR, MetS, and T2DM (Lee et al., 2010; Petersen et al., 2003, 2004). Optimal mitochondrial function is central to cell physiology. A wide range of chemicals has been reported to disturb mitochondrial function and cause mitochondrial toxicities and diseases (Vuda and Kamath, 2016; Wagner et al., 2008). Additionally, a series of recent
studies demonstrated the connections between various environmental chemicals and metabolic disorders (Neel and Sargis, 2011). In this chapter, we will provide evidence that environmental chemicals may induce mitochondrial dysfunction resulting in IR, T2DM, and MetS.
44.2 Health Hazard of Environmental Chemicals: A Short History Concerns about environmental chemicals began in 1962 after Rachel Carson published the monumental book entitled Silent Spring (Lytle, 2007). In this book, she claimed that the indiscriminate use of chemicals, especially pesticides, adversely affects the environment. For example, dichlorodiphenyltrichloroethane (DDT) was developed to prevent malaria epidemic by controlling mosquitoes, but its use is now prohibited due to causing human toxicity, cancer, and other illnesses. The US Environmental Protection Agency (EPA) and the United Nations Environment Programme (UNEP) were established in 1970 and 1972, respectively, to
Mitochondrial Dysfunction by Drug and Environmental Toxicants, Volume II, First Edition. Edited by Yvonne Will and James A. Dykens. © 2018 John Wiley & Sons, Inc. Published 2018 by John Wiley & Sons, Inc.
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additive enhancement of chemical actions as “mixture effect” or “cocktail effect.” Many of the synthetic organic chemicals are better known for causing weight loss at high levels of exposure, but much lower concentrations of these same chemicals have powerful weight‐gaining actions. For many years, the mechanisms by which some environmental chemicals acted at low doses were not well understood. There are two major concepts in EDC studies: low‐dose and nonmonotonicity. Low‐dose effects are defined by the National Toxicology Program (NTP) as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. Nonmonotonic dose response is a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined (Vandenberg et al., 2012), suggesting that low‐dose effects may be different, and sometimes even opposite, from high‐dose effects. Nonmonotonic responses and low‐dose effects are remarkably common in studies of natural hormones and EDCs. Hormones produced by the endocrine system are functioning at extremely low concentrations, comparable with the levels of EDCs. Natural hormone‐mimicking EDCs at low doses exert similar biological effects to hormones because they share the same receptor. Circulating natural hormones are present in three different forms: free (the active form of the hormone), bioavailable (bound weakly to proteins such as albumin), and inactive (bound with high affinity to proteins such as hormone binding proteins) (Vandenberg et al., 2012). Protein‐ bound hormones act as a natural buffering system, allowing the hormone to be accessible in the blood, but preventing large doses of physiologically active hormone from circulating. In contrast, the majority of a circulating EDC can be physiologically active because EDC‐specific binding protein is not present. Therefore, even a low concentration of an EDC can disrupt the natural balance of endogenous hormones in the circulation. Therefore, traditional criteria for chemical testing and safety determination need to be changed to protect human health.
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pay closer attention to environmental chemicals and human health. UNEP proposed to control “persistent organic pollutants (POPs),” defined as “chemical substances that persist in the environment, bio‐accumulate through the food chain, and pose a risk of adversely affecting human health and the environment.” Some POP chemicals such as pesticides, industrial chemicals, and by‐products have been banned or are strictly controlled from use and production under the Stockholm Convention (http:// chm.pops.int/TheConvention/ThePOPs/tabid/673/ Default.aspx). In 2009, the Endocrine Society published the landmark paper “Endocrine Disrupting Chemicals (EDC): An Endocrine Society Scientific Statement,” known as “EDC‐1” (Diamanti‐Kandarakis et al., 2009). Then, UNEP and the World Health Organization (WHO) copublished another landmark book, State of the Science of Endocrine Disrupting Chemicals in 2012. In 2015, the Endocrine Society published EDC‐2, The Endocrine Society’s Second Scientific Statement on Endocrine‐Disrupting Chemicals (Gore et al., 2015). EDC‐2 described the underlying mechanisms by which exposures during development in animals and humans lay the foundation for diseases later in life. Importantly, it provided a simplified operational working definition of EDCs: an exogenous chemical or mixture of chemicals that interferes with endogenous hormonal axes and induces metabolic disruption in vitro and in vivo. Unlike the early studies of EDCs, which focused on identifying chemicals to modulate the signal transduction of sex steroid and thyroid hormones, emerging data strongly suggest that EDCs disturb the signaling pathways critical for energy homeostasis, mitochondrial activities, and insulin signaling.
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44.3 Low‐Level Exposure to Multiple Chemicals
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Humans are exposed to a complex mixture of chemicals from various sources in everyday life. The exposure levels of individual environmental chemicals to the general population are far lower than in the case of environmental disasters such as chemical plant explosion, military personnel exposures, and occupational exposures. However, even low‐level exposure over decades to a complex cocktail of pollutants in air, water, food, consumer products, and buildings can have a significant effect on the health status of citizens (Commition, 2009). In other words, mixtures of dissimilarly acting chemicals may not be safe even if individual constituent chemicals are at levels below no observed adverse effect levels (NOAELs) or lowest observed adverse effect levels (LOAELs) (Kortenkamp et al., 2007). We refer to this
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44.4 POPs and Obesity Paradox POPs are lipophilic chemicals that accumulate in a dipose tissue and are hard to eliminate from contaminated environments and human bodies. POPs of concern at present are polychlorinated dibenzo‐p‐dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyl congeners (PCBs), organochlorine pesticides (OCPs), and brominated flame retardants (BFR). Simultaneous exposure to various POPs may cause obesity and diabetes as a mixture effect in the general population
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More than 800 chemicals may contain endocrine‐disrupting activity (Gore et al., 2015). Table 44.1 summarized the nature and health hazards of individual POPs and/or EDCs. We did not include heavy metals such as arsenic and cadmium in the table although they are known to be toxic to mitochondria (Prakash et al., 2016) and are causally associated with diabetes and cardiovascular diseases (Kuo et al., 2015; Moon et al., 2013). For better understanding the nature and distribution of EDCs, we categorized them into two groups: nonpersistent and persistent chemicals according to half‐life. Each group is then subdivided by usage or source. Nonpersistent chemicals, such as bisphenol A (BPA) and phthalates, released from widely used plastics and epoxy resins, are commonly detected in most populations. The herbicide atrazine and the fungicide vinclozolin are of great importance in agriculture and are easily excreted. Diethylstilbestrol (DES) and ethinyl estradiol (EE) are synthetic estrogen‐like compounds, which are used as drugs and are involved in carcinogenesis. Without accumulation in the body, nonpersistent EDCs still enhance the risk of diseases such as cancer, liver damages, and/or neurological disorders (Gore et al., 2015; Heindel et al., 2015). Owing to the short biological half‐life of nonpersistent EDCs, human epidemiological studies did not clearly show an association of the plasma or urine levels of EDCs with incidence of obesity and diabetes (James‐Todd et al., 2016; Lind et al., 2012; Sun et al., 2014). But several animal studies demonstrated that exposure to environmentally relevant doses of these compounds increased body weight, suggesting they are obesogens (Angle et al., 2013; Lim et al., 2009). Estrogen receptor has been thought to mediate their obesogenic activities, while adipocyte differentiation and adipogenesis might also be involved via
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44.5 Body Burden of Chemicals
various mechanisms (Biemann et al., 2012; Chamorro‐Garcia et al., 2012; Heindel et al., 2015). In contrast, persistent EDCs such as dioxins, OCPs, and other POPs are accumulated and stored in adipose tissue. The classification by persistency may help understand the “body burden,” which is defined as the total amount of environmental chemicals that are present in the human body at a given point in time. Body burden tests analyze the concentration of environmental chemicals in blood, urine, breast milk, and other fluids and tissues. This biomonitoring test tells us about the extent of our exposure to various substances, but not necessarily what the effects of this “burden” will be. Because of lipophilicity, a large amount of POPs can be stored in fat tissue depot that may sequester those toxic persistent chemicals to protect vital organs. Upon lipolysis of stored fat, the lipophilic chemicals can also be released into blood from the storage. Therefore, weight loss in the obese elderly with high serum concentrations of POPs may carry some risk of damage on vital organs by the released chemicals although weight loss may be beneficial among the obese elderly with low POP concentrations. To prevent the surge of persistent chemicals into blood, we believe that the biomonitoring test for the chemicals should be performed during weight control or health checkup processes. At the same time, sampling of blood or urine should be done at certain fixed times of the day, like early in the morning without stress, for consistent and reliable monitoring. This classification may also be useful to locate EDCs geographically. Some insecticides are used mostly in rural agricultural areas, while many other POPs are associated with industrial activities.
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(Lee et al., 2006b, 2011), which posited environmental “obesogen hypothesis.” This hypothesis postulates that certain EDCs or POPs that interfere with the body’s adipose tissue biology, endocrine hormone systems, or central hypothalamic–pituitary–adrenal axis are derailing the weight control homeostasis (Grun and Blumberg, 2009; Heindel et al., 2015). It is important to note that POPs in fat tissue, not obesity itself, may contribute to the development of IR and T2DM. An “obesity paradox” has been documented that the overweight and obese elderly have better prognosis than those with normal body weight. This may reflect the relative safety of storing the harmful lipophilic POPs in adipose tissue rather than in bloodstream, which damage other critical organs (Hong et al., 2012).
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44.6 Diabetes Mellitus, Insulin Resistance, and Metabolic Syndrome Diabetes is defined by high blood glucose level. In normal physiology, high blood glucose should only occur with low level of insulin, the most important glucose‐ lowering hormone. However, subjects with T2DM frequently have high blood glucose levels with rather high serum insulin levels, suggesting a development of IR in the body. Current paradigm understanding of diabetes is that it occurs when insulin production cannot overcome IR induced by high fat diet and inactivity. Therefore, diabetes is characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. MetS is a cluster of the most dangerous cardiovascular risk factors: hyperglycemia, prediabetes (IR), abdominal obesity, hypertension, and dyslipidemia (Huang, 2009). Reaven named the clustered state of risk factors as syndrome X in 1993 (Reaven, 1988, 1993). In 2001, the Adult
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Table 44.1 The nature of common EDCs or POPs and their known health hazards. Chemicals
Nature
Known health hazards
Nonpersistent
Bisphenol A
Used in plastics and resins
Estrogenic, obesogenic, neurological effects, adverse thyroid hormone action, reproductive and developmental effects
Phthalates
Plasticizers
Carcinogen, liver damage, reproductive and developmental effects, asthma, obesogen
Atrazine
Chlorotriazine herbicide
Endocrine, respiratory, and nervous system targets, liver damage, obesogenic; increases aromatase expression; antiandrogenic
Vinclozolin
Dicarboximide fungicide
Antiandrogenic activity, male reproductive and neurological effects, transgenerational reproductive effects, potential carcinogen
Diethylstilbestrol (DES)
Used as drugs; nonsteroidal synthetic estrogen
Transplacental carcinogen, teratogen
Ethinyl estradiol
Used as drugs; synthetic derivative of 17β‐estradiol
Cardiovascular disease, cerebrovascular disease, thromboembolic disease, gallbladder disease, carcinogenic
Methoxychlor
Organochlorine insecticide
DDT, DDD, and DDE
Organochlorine insecticides and its metabolite
Carcinogen, central nervous system, kidney, liver and peripheral nervous system effects
TCDD or dioxin
Released from industries; most toxic among dioxins or PCDDs
Liver damage, weight loss, atrophy of thymus gland, immunosuppression, reproductive effects, and cancer
PCDFs
Released from industries; organochlorines
Developmental teratogen and carcinogen
Released from industries; organochlorines; 209 possible congeners
Carcinogen, chloracne, stomach and liver damage, reproductive and nervous system effects and thyroid injury, stimulation of fat production; impairs glutamate pathways, mimics estrogen, antiestrogenic activity, and so on
Released from industries; pentaBDE, octaBDE, decaBDE
Alters TH synthesis
Released from industries; perfluorochemical
Liver and mammary gland developmental and immune system toxicant, carcinogen
Rarely detected
Estrogenic activity; binds ER; sexually dimorphic behavior Stimulates glucocorticoid receptor; decreases testosterone levels; induces testosterone hydroxylases; modulates binding of ligand to TRE; weakly binds AhR
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PBDEs
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Aldrin/dieldrin; chlordane and related compounds; endrin; mirex; heptachlor; hexachlorobenzene; toxaphene
Central nervous system depression, damage to liver and kidney, developmental and reproductive effects in animals, transgenerational kidney and ovary disease, obesogen; binds ER
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DDD, dichloro‐diphenyldichloro‐ethane; DDE, dichloro‐diphenyldichloro‐ethylene; DDT, p,p′‐dichloro‐diphenyltrichloro‐ethane; DES, diethylstilbestrol; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PCDD, polychlorinated dibenzo‐p‐dioxin; PCDFs, polychlorinated dibenzo‐p‐furans; PFOA, perfluorooctanoic acid; PFOS, perfluoro‐octane yl sulfonic acid; TCDD, tetrachloro‐dibenzo‐p‐dioxin.
Treatment Panel III (ATP III) of the National Cholesterol Education Program of the United States made different diagnostic criteria (Table 44.2), which are now widely used (Expert Panel on Detection and Treatment of High Blood Cholesterol in 2001). It should be noted that the ATP III was created to define MetS for clinical purpose.
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Although the MetS is frequently considered as a disease entity, it is a diagnostic category, identifying individuals to initiate lifestyle changes with the goal of decreasing risks of cardiovascular disease, the most important cause of death (Mortality and Causes of Death 2015). IR is a pathophysiological state in which body and cells fail to
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44.7 Association of POPs with Diabetes and Metabolic Syndrome
respond normally to insulin. But IR is found not only in diabetes but also in many other disease states, such as dyslipidemia, hypertension, and neurodegenerative diseases (Reaven, 1988; Shen et al., 1970), suggesting that IR may be a critical contributor in developing these diseases. The primary value of the concept of IR is that it provides a framework for placing a substantial number of apparently unrelated biological events into a pathophysiological construct (Reaven, 2005). This point is crucial in understanding the association between exposure to environmental chemicals and IR or MetS, because high exposure to environmental chemicals frequently occurs together with IR.
44.7.1 Ecological Studies
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In 2002, Baillie‐Hamilton hypothesized that the toxic chemicals might be obesogenic, based on an observation that there is a parallel increase of chemical toxin production and incidence of obesity (Baillie‐Hamilton, 2002). The parallelism was firmly established with diabetes in 2011 by Neel and Sargis (2011). Figure 44.1 demonstrated that obesity and diabetes epidemic in United States might be closely related to the increasing production and usage of synthetic organic chemicals. These data suggest that the human exposure to the chemical compounds is strongly suspected as a causal factor in developing the diseases (Heindel et al., 2017).
Abdominal obesity
Waist circumference (WC)
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Table 44.2 ATP III criteria for diagnosing the metabolic syndrome.
MetS criteria
44.7.2 Epidemiologic Studies on the Association between POPs and T2DM
Men: WC > 40 inches (102 cm) Fasting glucose
Dyslipidemia
Triglycerides (TG)
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>110–126 mg/dL (6.1–7.0 mmol/L)
Prior to Baillie‐Hamilton’s report, there have been many anecdotal reports linking exposure to POPs and development of diabetes. However, epidemiologic studies began only recently to prove the association between serum levels of POPs and T2DM. Lee et al. (2006b, 2007a, b) analyzed US NHANES 1999–2002 database and provided critical evidence for the involvement of serum concentrations of POPs in obesity or diabetes. They showed that the sum of 6 most frequently detected POPs (2,2′,4,4′,5,5′‐ hexachlorobiphenyl, 1,2,3,4,6,7,8‐heptachlorodibenzo‐p‐ dioxin, 1,2,3,4,6,7,8,9‐octachlorodibenzo‐p‐dioxin, oxychlordane, p,p′‐dichlorodiphenyltrichloroethane, and
>150 mg/dL (1.7 mmol/L)
High‐density lipoprotein cholesterol (HDL‐C)
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Men: 130/80 mm Hg
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Chemical production
8 (40)
Diabetes (%) Obesity (%)
6 (35)
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4 (30)
100 2 (25)
Prevalence (%)
Hyperglycemia
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Experimental data are needed to confirm the causality of low‐level exposure to POPs, which will shed new light on the pathogenesis of diabetes. Lim et al. (2009) reported that atrazine, a chlorotriazine herbicide when given at low concentration, caused IR and induced mitochondrial dysfunction in skeletal muscle in rats, when fed with high fat diet for 2 months. Ruzzin et al. (2010) found that feeding contaminated Atlantic salmon oil to rats for 28 days induced IR and fatty liver. In addition, it induced downregulation of two master regulators of lipid homeostasis, insulin‐induced gene‐1 and Lpin1, as well as genes related to mitochondrial function, including peroxisome proliferator‐activated receptor‐γ (PPARγ) coactivator‐1α (PGC‐1α), citrate synthase, succinate dehydrogenase A, and medium‐chain acyl‐CoA dehydrogenase, in the liver of rats. In addition, various EDCs at low doses were studied for their diabetogenic or obesogenic effects (Heindel et al., 2017; Vandenberg et al., 2012). For example, BPA alone or in combination with DES induced either diabetes or obesity in animal studies. DDT, phthalate metabolites, PCBs (−77, −126, −153), perfluorooctanoic acid (PFOA), perfluoro‐octane yl sulfonic acid (PFOS), tributyltin (TBT), and tetrachlorodibenzo‐p‐dioxin (TCDD), alone or in combinations, are also listed as causative agents for obesity and diabetes (Heindel et al., 2015, Ngwa et al., 2015; 2016). In fact, there are lots of EDCs for which high‐dose toxicology studies have been performed
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44.7.4 Cause–Effect Relationship between Exposure to POPs and the Onset of T2DM or MetS
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Despite many reports, there is no direct evidence that the exposure to POPs is the cause of T2DM or MetS in humans. There are several reasons. Traditionally, a cause of a disease is established when the suspected causative agent meets Koch’s three principles: (i) that agent is always present in the persons with a specific disease, (ii) that agent could be isolated in pure form, and (iii) that transfer of that pure agent reproduces disease in susceptible animals. These principles are not applicable here, because environmental pollutants are enormously diverse chemicals with varying toxicities and the diseases they cause are not specific, but complex. POPs are present in the environment as mixtures of chemicals, some with known toxicities, but potentially others with many unknown ones; hence, they cannot qualify as a specific “causative agent.” It is estimated that about 10,000 new chemicals are synthesized and released to our environment every year without evaluation of their toxicity in humans. Also, there is no good method of evaluating biological or toxicological effects of mixtures of POPs, to which people are exposed. T2DM itself, a component disease of MetS, is a “complex disease,” meaning that T2DM may have many “causes.” It is reasonable to hypothesize that clustering of complex diseases in a person may be a result of introducing a mixture of POPs into our body.
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44.7.3 Animal Experiments: Low‐Dose Exposure to Chemicals and Development of Diabetes
and the NOAEL has been derived, but no animal studies in the low‐dose range. Also, several hundred additional EDCs where no significant high‐ or low‐dose testing have been performed. Table 44.3 summarizes a limited selection of the environmental chemicals that are related with obesity and T2DM, nuclear receptors involved in function, and the reported effects on mitochondria.
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trans‐nonachlor) among US citizens was clearly associated with prevalence of diabetes (Lee et al., 2006b, 2014), which made quite a stir to the scientific community. Cross‐sectional and case–control studies have reported strong associations of T2DM and MetS with OCPs, dioxins, PCBs, and/or dichlorodiphenyldichloroethylene (DDE) (Taylor et al., 2013). There is less indication of an association between T2DM and other non‐organochlorine POPs, such as perfluoroalkyl acids and brominated compounds. There are more than 80 epidemiological studies, showing that POPs are related to altered glucose homeostasis, IR, and/or MetS. As this chapter aims to introduce this field, authors recommend other review articles (Gore et al., 2015; Lee et al., 2014; Taylor et al., 2013) for further details, such as EDC‐2 (Gore et al., 2015) and the NTP workshop review (Taylor et al., 2013; Thayer et al., 2012), which was organized by US NTP in 2011. In summary, epidemiologic studies have provided sufficient overall evidence for proving a positive association between some organochlorine POPs, BPA, phthalates, organotins, and arsenics with T2DM.
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44.8 Toxic and Biological Effects of Some POPs via AhR Some POPs are known to induce adverse effects on various biological systems via binding to aryl hydrocarbon receptor (AhR), a cytosolic nuclear receptor present in most vertebrate tissues (Schlezinger et al., 2010). AhR is a ligand‐activated transcription factor belonging to the basic helix‐loop‐helix (bHLH)/Per‐Arnt‐Sim family (Beischlag et al., 2008). Ligand binding to AhR activates the transcription of multiple genes including cytochrome P450 (CYP) members, CYP1A1/2 and CYP1B1, and ligand‐metabolizing enzymes. Induction of CYP enzymes enhances the metabolism and clearance of AhR ligands
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POPs/209 possible congeners (e.g., PCB126, PCB169)
POPs
POPs/DDT, DDE, endrin, heptachlor, mirex, toxaphene
PBB, PBDE
PFOA, PFOS
DEHP, DBP, DEP, MEHP
BPA
TBT, TPT, TPTO
PCBs
HCB
OCPs
BFR
PFCs
Phthalates
BPA
Organotins
MetS, obesity, and T2DM
In food. Fungicide in paints and heat stabilizer in polyvinyl chlorides, pesticide, wood preservation
Plastics and epoxy resins
Plasticizers, adhesives, and personal care products
Components of lubricants, nonstick coatings, and stain‐ resistant compound
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Induced adipogenesis (mice), increased fat cell differentiation, increased lipid accumulation
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Altered morphology, membrane potential, mass, etc. ROS generation
Uncoupler, mitochondria swelling, inhibiting succinate dehydrogenase
Alteration in energy metabolism genes, ATPase, OXPHOS complexes 1 and IV, ROS generation
Impaired mitochondrial bioenergetics, membrane potential, OCR, calcium release, mitochondrial swelling, and ATP levels
Reduced energy expenditure, impaired thermogenesis
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ROS generation, decreased membrane potential, ATP level. Inhibition of OXPHOS complexes I, II, and IV
Mitochondrial fragmentation, decreased OCR, ROS generation, decreased membrane potential, ATP level
Mitochondrial dysfunction
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PPARγ, RXR
Obesity
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Increased body weight (mice, rat), Induced adipogenesis
ERs, AR, TR, GR
Diabetes, insulin resistance, childhood obesity, liver abnormalities
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Reduced plasma insulin and leptin levels (mice), increased rate of adipocyte differentiation
PPARs, CAR/ PXR, GR
Obesity, insulin resistance
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ERs, AR, PPARs
Weight gain and increased serum insulin and leptin levels (mice), increased adipocyte differentiation
Alters lipolysis and glucose oxidation (rat)
PXR, ERs, TR
Increased cholesterol level, offspring obesity
Associated with MetS, obesity, and T2DM
Glucose intolerance, hyperinsulinemia, dyslipidemia, altered bile acid metabolism (rat), gender differences
Obesity in infancy and childhood
Altered thyroid function, Altered metabolism, bioaccumulation in fat cells
Affects energy metabolism, accumulation of visceral fat, inflammation
Animal studies
AhR, PPARγ, ERs
AhR, TH‐ responsive genes
AhR, PPARγ, ERs
AhR, PPARγ, ERs
Potential mechanism: nuclear receptor
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MetS, obesity, T2DM, and childhood obesity
Pesticides, insecticides
Chemicals applied to furniture and electronics
Overweight. Obesity in offspring
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MetS, obesity, T2DM, childhood obesity
Fungicide, a byproduct of the industrial chemicals (e.g., CCl4)
Coolants, plasticizers, and flame retardants
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In food, air pollution, incomplete combustion of fossil fuels
Human epidemiological studies
AhR, aryl hydrocarbon receptor; AR, androgen receptor; BFR, brominated flame retardant; BPA, bisphenol A; CAR, constitutive androstane receptor; DBP, dibutyl phthalate; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; DEHP, diethylhexyl phthalate; DEP, diethyl phthalate; ER, estrogen receptor; GR, glucocorticoid receptor; HCB, hexachlorobenzene; MEHP, bis(2‐ethylhexyl) phthalate; MetS, metabolic syndrome; OCPs, organochlorine pesticides; OCR, oxygen consumption rate; PBDE, polybrominated diphenyl ether; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo‐p‐dioxins; PCDF, polychlorinated dibenzofurans; PFC, polyfluoroalkyl compound; PFOA, perfluorooctanoate; PFOS, perfluoro‐ octane yl sulfonic acid; PPAR, peroxisome proliferator–activated receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; T2DM, type 2 diabetes; TBT, tributyltin chloride; TCDD, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin; TPTO, bis(triphenyltin) oxide; TR, thyroid hormone receptor.
POPs/210 dioxins and furans, 17 highly toxic (e.g., TCDD)
PCDD, PCDF
Type or source
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Examples
Chemical
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Table 44.3 Environmental chemicals associated with T2DM and obesity.
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adenosine triphosphate (ATP) synthase in mitochondria and this interaction was lost upon 10 nM TCDD treatment (Tappenden et al., 2011). Recently, it was found that AhR was present in the intermembrane space of mitochondria. TCDD exposure at 10 nM induced a degradation of mitochondrial AhR, reduction of respiratory capacity, and alteration of mitochondrial proteome in an AhR‐dependent manner (Hwang et al., 2016). The AhR was also suggested as a regulator of the influx of electrons into electron transfer chain to maintain cellular respiratory capacity. A study using C2C12 skeletal myoblast cells demonstrated that nongenomic AhR signaling generated TCDD‐induced mitochondrial toxicities (Biswas et al., 2008). Therefore, both genomic and nongenomic AhR signaling would affect mitochondrial toxicities by prolonged TCDD exposure as the TCDD‐induced transcription‐independent retrograde signaling from the mitochondria to the nucleus.
44.9 Insulin Resistance and Mitochondrial Dysfunction Impaired mitochondrial function is linked with aging as well as many pathological states including IR, T2DM, MetS, obesity, and cancer (Petersen et al., 2003; Vuda and Kamath, 2016). Mitochondria are locations for metabolism of glucose, fatty acid, and protein and calcium homeostasis and are the control tower for cell death. When mitochondrial oxygen consumption is decreased due to altered metabolism, there is an increase in reactive oxygen species (ROS) that can impair different types of molecules and cells. Reversely, insulin is able to stimulate mitochondrial function by enhancing mitochondrial dynamics via the Akt‐mTOR‐NFkappaB‐ Opa‐1 signaling pathway (Parra et al., 2014). Several human studies suggest that mild mtDNA variants, haplogroup or single‐nucleotide polymorphism, may be associated with aging or diseases although mechanistic evidence at the molecular level is lacking. Some human mtDNA variations are associated with IR. Several population studies showed that mitochondrial haplogroup N9a confers resistance against T2DM, MetS (Fuku et al., 2007; Hwang et al., 2011; Tanaka et al., 2007), and diabetic complications (Niu et al., 2015). Conplastic animals with the same nuclear genome but with different mtDNAs show profound transcriptomic, proteomic, and metabolomic differences (Latorre‐Pellicer et al., 2016). These mtDNA variations were linked to risk factors for T2DM, reduced mitochondrial oxidative phosphorylation (OXPHOS) enzyme levels, IR, cardiac hypertrophy, and systolic dysfunction (Houstek et al., 2014; Pravenec et al., 2007). Recent systematic characterization of conplastic mice throughout their lifespan showed that the mtDNA haplotype profoundly influences mitochondrial
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in liver. Since 2,3,7,8‐TCDD is the most potent AhR ligand with high affinity, AhR is called the dioxin receptor. AhR is able to bind a wide range of structurally divergent chemicals, suggesting that AhR contains promiscuous ligand binding site (Denison et al., 2011). Dennison et al. (Denison and Nagy 2003; Denison et al., 2002) reported exogenous AhR ligands covering diverse synthetic environmental chemicals or naturally occurring compounds such as indole‐3‐carbinol (I3C) and flavonoids using AhR‐mediated reporter gene assays. I3C dietary AhR ligand provided from vegetables protects the host by an induction of active immunologic tolerance in the intestine (Li et al., 2011). A tryptophan catabolite, kynurenine, has been identified as an endogenous AhR ligand that is constitutively generated in human brain tumor cells (Opitz et al., 2011). AhR ligands mediate a wide range of biological and toxic effects, including tumor promotion; teratogenicity; immuno‐, hepato‐, cardio‐, and dermal toxicity; wasting; lethality; and alteration of endocrine homeostasis (Denison et al., 2011). The molecular mechanisms underlying AhR ligand action have been studied with multiple molecules interacting with AhR (Denison et al., 2011). In classical mechanism of AhR‐dependent gene activation, the cytosolic AhR forms a complex with HBV X‐associated protein 2 (XAP2), Hsp90, and p23 (Shetty et al., 2003), which are displaced by Arnt after binding to the ligand. The resulting AhR/Arnt dimer binds to a drug response element (DRE) (5′‐TNGCGTG‐3′) on the promoters of target genes such as CYPs, aldehyde dehydrogenase 3 (ALDH3), AhR repressor (AhRR), p27kip1, and so on. AhRR is another bHLH/Per‐Arnt‐Sim transcription factor, which is also induced by AhR/Arnt complex upon binding on the DRE of AhRR promoter. Unlike other target genes, the transactivation domain‐deficient AhRR functions as a naturally occurring dominant negative factor by competing with AhR for heterodimer formation with Arnt (Evans et al., 2008). Therefore, AhRR and AhR constitute a regulatory loop affecting each other’s transcriptions to maintain a homeostasis. In various human malignant tissues, AhRR mRNA is downregulated due to methylation of DRE sites of the promoter, suggesting that AhRR might play a role as a tumor suppressor (Zudaire et al., 2008). Despite accumulation of evidence showing that many environmental chemicals are AhR ligands and destroy mitochondrial activities, it is not clearly understood whether their toxic effects are linked to mitochondrial damages. TCDD increases mitochondrial ROS production, which was observed in liver mitochondria of CYP1A1 null mice, but not in those of AhR null mice (Senft et al., 2002). The AhR‐dependent oxidative stress in mitochondria mediated the concomitant mitochondrial DNA (mtDNA) cleavage (Shen et al., 2005). Proteomic analysis of AhR‐interacting proteins showed that ligand‐ absent AhR was interacting with ATP5α, a subunit of
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Persistent Organic Pollutants, Mitochondrial Dysfunction, and Metabolic Syndrome
There are many different ways to damage mitochondria. Environmental chemicals in serum may damage mitochondria of insulin‐sensitive organs such as the adipose
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44.9.1 Mitochondrial Damages Induced by Environmental Chemicals
tissue, pancreas, liver, and muscles, which fail to function properly. It is not clear how environmental chemicals mediate mitochondrial dysfunction and IR although many environmental chemicals have been identified as AhR ligands. There are only a handful studies on how POPs damage mitochondria. In addition to the results described in Section 44.7.3, TCDD also induced oxidative stress (Shen et al., 2005), mitochondrial pathways of apoptosis (Camacho et al., 2005), damaged mitochondrial OXPHOS and ATP production, and disrupted cristae structure in mitochondria in cardiomyocytes (Neri et al., 2011). We also demonstrated that TCDD and diabetic serum suppressed the basal oxygen consumption rate and ATP turnover rate of mitochondria (Park et al., 2013). TCDD at pM concentrations induced mitochondrial fragmentation and dysfunction measured by intracellular ATP concentration by luciferase–luciferin reaction and 5‐(and‐6)‐ chloromethyl‐2′,7′‐dichlorodihydrofluorescein diacetate,
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proteostasis and ROS generation, insulin signaling, obesity, and aging parameters and mitochondrial dysfunction (Latorre‐Pellicer et al., 2016). In fact, blood mtDNA content was decreased and mitochondrial function in skeletal muscle was reduced in subjects with IR, offsprings of T2DM, or prediabetes (Petersen et al., 2003; Shoar et al., 2016). When mtDNA was artificially depleted using ethidium bromide, cellular glucose uptake and glucose metabolism were critically impaired (Park et al., 2001). Therefore, we believe that mitochondrial function needs to be maintained during lifetime to ensure healthy status (Lee et al., 2010).
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Figure 44.2 TCDD treatment‐induced mitochondrial damages. C2C12 cells were treated with various concentrations of TCDD for 72 h. Intracellular ATP contents (a) and ROS generation (b) were determined (*p
