Journal of
Endocrinology
L Marroqui, E Tudurí et al.
239:2
Mitochondria and endocrinedisrupting chemicals
R27–R45
REVIEW
Mitochondria as target of endocrine-disrupting
chemicals: implications for type 2 diabetes
Laura Marroqui*, Eva Tudurí*, Paloma Alonso-Magdalena, Iván Quesada, Ángel Nadal and
Reinaldo Sousa dos Santos
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Institute of Bioengineering, Miguel
Hernández University of Elche, Alicante, Spain
Correspondence should be addressed to Á Nadal or R S dos Santos: nadal@umh.es or r.sousa@umh.es
*(L Marroqui and E Tudurí contributed equally to this work)
Abstract
Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin
resistance and pancreatic β-cell dysfunction or death. Among several environmental
factors contributing to type 2 diabetes development, endocrine-disrupting chemicals
(EDCs) have been receiving special attention. These chemicals include a wide variety
of pollutants, from components of plastic to pesticides, with the ability to modulate
endocrine system function. EDCs can affect multiple cellular processes, including
some related to energy production and utilization, leading to alterations in energy
homeostasis. Mitochondria are primarily implicated in cellular energy conversion,
although they also participate in other processes, such as hormone secretion and
apoptosis. In fact, mitochondrial dysfunction due to reduced oxidative capacity, impaired
lipid oxidation and increased oxidative stress has been linked to insulin resistance
and type 2 diabetes. Herein, we review the main mechanisms whereby metabolismdisrupting chemical (MDC), a subclass of EDCs that disturbs energy homeostasis, cause
mitochondrial dysfunction, thus contributing to the establishment of insulin resistance
and type 2 diabetes. We conclude that MDC-induced mitochondrial dysfunction, which
is mainly characterized by perturbations in mitochondrial bioenergetics, biogenesis
and dynamics, excessive reactive oxygen species production and activation of the
mitochondrial pathway of apoptosis, seems to be a relevant mechanism linking
MDCs to type 2 diabetes development.
Key Words
f endocrine-disrupting
chemicals
f metabolism-disrupting
chemical
f insulin resistance
f type 2 diabetes
f mitochondria
Journal of Endocrinology
(2018) 239, R27–R45
Introduction
Type 2 diabetes (T2D) is a chronic, lifelong condition
characterized by hyperglycaemia resulting from persistent
insulin resistance (IR) and/or insufficient insulin production
due to β-cell dysfunction or death (Prentki & Nolan 2006).
T2D is a heterogeneous, multi-factorial syndrome in which
genetic predisposition and environmental factors account
for its development. Over the last years, a class of chemical
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pollutants named endocrine-disrupting chemicals (EDCs)
has been associated with several metabolic diseases,
including obesity and T2D (Alonso-Magdalena et al.
2011, Neel & Sargis 2011, Gore et al. 2015, Braun 2016,
Heindel et al. 2017). This association seems plausible as
these chemicals can alter energy metabolism by affecting
multiple cellular events in different organelles, including
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endoplasmic reticulum (ER) and mitochondria (Meyer
et al. 2013, Nadal et al. 2017, Rajamani et al. 2017).
Mitochondria are essential for the normal cellular
function in eukaryotic organisms. Although mitochondria
are best known as the powerhouse of the cell due to their
crucial role in cellular energy production via oxidative
phosphorylation (OXPHOS), these organelles are also key
players in other critical cellular processes. For instance,
mitochondria are implicated in hormone secretion
(Chow et al. 2017), generation of reactive oxygen species
(ROS) (Brand 2016) and cell death (Fulda et al. 2010).
Such involvement in a wide variety of processes places
the mitochondria at the epicenter of many disorders,
including aging and metabolic diseases (Fosslien 2001).
A growing body of evidence has linked mitochondrial
dysfunction to T2D (reviewed in: Patti & Corvera 2010,
Szendroedi et al. 2011, Gonzalez-Franquesa & Patti 2017,
Fex et al. 2018). Essentially, alterations in mitochondrial
bioenergetics, biogenesis and dynamics, as well as excessive
ROS production, can impact metabolic homeostasis,
which might contribute to the establishment of IR and,
subsequently, T2D (Petersen et al. 2003, 2004, Houstis
et al. 2006, Anderson et al. 2009, Jheng et al. 2012).
Thus, due to its vital relevance for the proper
physiology and survival of eukaryotic cells, it seems
logical that pollutants targeting mitochondria would lead
to harmful effects, especially on metabolic homeostasis.
In fact, the term metabolism-disrupting chemical (MDC)
has been recently proposed to refer to a particular class
of EDCs that disturbs energy homeostasis and, therefore,
affects the susceptibility to metabolic disorders (Heindel
et al. 2017). Bisphenol A (BPA), chlorpyrifos, tributyltin
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and 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are some of
the most common MDCs identified up to date.
In this review, we first highlight the recent evidence
correlating EDCs with T2D development. We then outline
how mitochondria dysfunction in different tissues
involved in metabolic homeostasis is linked to IR and
T2D development. Finally, we examine the deleterious
effects of MDCs on different mitochondrial processes and
discuss how MDC-induced mitochondria dysfunction
may lead to IR and T2D. Herein, we indicate doses and
type of exposure (e.g. perinatal or during adulthood)
for most examples cited, as this information is critical
for understanding MDCs effects. To contextualize the
reader, we provide a table with the reference doses (RfD)
provided by the United States Environmental Protection
Agency (EPA) (Table 1) as well as two reports providing
comprehensive information on EDC biomonitoring data
(CDC 2009, CDC 2018).
Introduction to mitochondria
Before discussing the evidence connecting mitochondrial
dysfunction to T2DM, and how MDCs affect mitochondria,
we first summarize some key mitochondrial processes
(Fig. 1).
Bioenergetics
Mitochondria are often recognized as the powerhouse of
the cell, as they are responsible for most part of the cellular
energy produced. It is in the mitochondria that sugars,
proteins and fats are converted into energy in the form
Table 1 Reference doses (RfD) for some MDCs.
Chemical
RfD (mg/kg/day)
Source/Ref
Arsenic
Atrazine
BBP
BPA
Cadmium
3 × 10−4
EPA_Arsenic, inorganic; CASRN 7440-38-2
EPA_Atrazine; CASRN 1912-24-9
EPA_Butyl benzyl phthalate; CASRN 85-687
EPA_Bisphenol A; CASRN 80-05-7
EPA_Cadmium; CASRN 7440-43-9
Chlorpyrifos
DEHP
PFOA
PFOS
TCDD
Tributyltin oxide
3.5 × 10−2
2 × 10−1
5 × 10−2
5 × 10−4 (water)
1 × 10−3 (food)
Withdrawn
2 × 10−2
2 × 10−5
2 × 10−5
7 × 10−10
3 × 10−4
EPA_Chlorpyrifos; CASRN 2921-88-2
EPA_Di(2-ethylhexyl)phthalate (DEHP); CASRN 117-81-7
EPA_PFOA
EPA_PFOS
EPA_2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), CASRN 1746-01-6
EPA_Tributyltin oxide (TBTO); CASRN 5635-9
According to the United States Environmental Protection Agency (EPA), the reference dose is defined as ‘an estimate (with uncertainty spanning perhaps
an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk
of deleterious effects during a lifetime’. The readers are also referred to two reports from the Centers for Disease Control and Prevention (CDC)
providing comprehensive information on EDC biomonitoring data (CDC 2009, CDC 2018).
BBP, butyl benzyl phthalate; BPA, bisphenol A; CASRN, Chemical Abstracts Service Registry Number; DEHP, di(2-ethylhexyl)phthalate; PFOA,
perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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A
B
C
D
Figure 1
Schematic representation of some mitochondrial functions. (A) Mitochondrial bioenergetics. The tricarboxylic acid cycle (TCA), which takes place in the
mitochondrial matrix, generates NADH and FADH2, whose free energy will be used to transport electrons in the electron transport chain (ETC, located in
the inner mitochondrial membrane). Most part of the free energy coming from the electron transfer is used to form an electrochemical gradient (Δψm)
that drives the synthesis of ATP by the ATP synthase. Q and c: ubiquinone and cytochrome c, respectively. (B) Mitochondrial dynamics: mitochondrial
fusion (left), which generates large, interconnected mitochondrial networks, is mainly governed by the dynamin-related proteins, mitofusins 1 and 2
(MFN1 and MFN2) and optic atrophy 1 (OPA1). On the other hand, mitochondrial fission (right) leads to fragmented, separated mitochondria. This
process is regulated by several proteins, including dynamin-related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and the mitochondrial fission
factor (MFF). (C) Mitochondria ROS generation and antioxidant activity. Due to its redox activity, the ETC generates reactive oxygen species (ROS) as a
consequence of electron leak during the oxidative phosphorylation. The figure depicts the main sites of ROS production in the ETC, i.e. complexes I and
III. Of note, there are at least 11 different sites linked to ROS production in the mitochondria, such as the α-ketoglutarate dehydrogenase and the
glycerol 3-phosphate dehydrogenase. Complexes I and III generate superoxide radical (O2·−), which can be dismutated to hydrogen peroxide (H2O2) by
the enzymes superoxide dismutase (SOD) 1 (CuZnSOD, located in the intermembrane space) and 2 (MnSOD, located in the mitochondrial matrix). Other
antioxidant enzymes, such as catalase (CAT) and glutathione peroxidase (GPx), can decompose H2O2 into H2O and/or O2. (D) Mitochondrial pathway of
apoptosis. After an apoptotic stimulus, activated BH3-only proteins translocate to mitochondria where inactivate anti-apoptotic BCL-2 proteins and
activate pro-apoptotic BAX and BAK. BAX oligomerization in the outer mitochondrial membrane (OMM) leads to OMM permeabilization and release of
cytochrome c (c) and SMAC/DIABLO (S) from the intermembrane space into the cytosol. Under certain conditions (e.g. glucose deprivation and ischemia/
reperfusion injury), long-lasting opening of the mitochondrial PTP may also contribute to cytochrome c release. In these situations, prolonged PTP
opening leads to mitochondrial dysfunction (e.g. depolarization, and inhibition of oxidative phosphorylation and ATP synthesis) and matrix swelling,
which, in turn, causes outer mitochondrial membrane rupture and release of pro-apoptotic factors, including cytochrome c (consecutive arrows). Once in
the cytosol, cytochrome c drives caspase activation, which will culminate in activation of apoptosis.
of ATP via two metabolic processes, namely tricarboxylic
acid cycle (TCA) and OXPHOS. The free energy carried by
the coenzymes NADH and flavin adenine dinucleotide
(FADH2) is used to transport electrons in the electron
transport chain (ETC), which is composed of four
multipolypeptide enzyme complexes (complexes I to IV)
and two electron carriers (ubiquinone and cytochrome c).
Much of the free energy coming from the electron transfer
is used to form an electrochemical gradient that drives the
phosphorylation of ADP by the ATP synthase, an event
that is coupled to oxygen consumption (chemiosmotic
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model proposed by Mitchell 1961). However, part of this
energy may be ‘lost’ due to proton leak, which may result
from the return of protons to the matrix independently of
the ATP synthase or be catalyzed by specific mitochondrial
proteins, such as the adenine nucleotide translocase and
the uncoupling proteins (UCPs) (Jastroch et al. 2010).
Biogenesis
Mitochondrial biogenesis is a tightly regulated process
whereby cells increase their mtDNA content, mitochondrial
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mass and activity in response to different physiological
conditions.
Under certain physiological or stressful conditions,
activation of different signaling cascades culminates with
the activation of transcription factors and co-regulators
encoded by both nucleus and mitochondria. From the
nuclear side, nuclear respiratory factors 1 and 2 (NRF1
and NRF2) are the two major transcription factors,
directly modulating the expression of the mitochondrial
transcription factor A (TFAM) and transcription factor B
proteins (TFBs), two key regulators of the transcription and
replication of mtDNA (Gleyzer et al. 2005, Scarpulla 2008).
Mitochondrial biogenesis is coordinated by members
of the peroxisome proliferator-activated receptor (PPAR)
coactivator-1 (PGC-1) family of coactivators, namely
PGC-1α (PPARγ coactivator-1α), PGC-1β (PPARγ coactivator1β) and PRC (PGC-1 related coactivator) (Puigserver et al.
1998, Wu et al. 1999, Andersson & Scarpulla 2001, Lin
et al. 2002). PGC-1α is considered the master regulator
of mitochondrial biogenesis, as its activation leads to
activation of several transcription factors, such as PPARs,
NRF1/NRF2, estrogen-related receptors (ERRα, ERRβ, ERRγ)
and thyroid hormone receptors (TRα and TRβ) (Puigserver
& Spiegelman 2003, Scarpulla 2011).
Dynamics
Mitochondria are very dynamic organelles, exhibiting a
wide variety of shapes, size and location that can change
within a few seconds or minutes (Twig et al. 2010, Picard et al.
2016). These characteristics are related to active, regulated
processes called mitochondrial fission and fusion (also
known as mitochondrial dynamics), as well as the ability
of mitochondria to build extensive intracellular networks
through the formation of a tubular reticulum (BereiterHahn 1990, Scott & Youle 2010, Prasai 2017). A proper
control of mitochondrial dynamics is very important for
several biological processes, such as regulation of neuronal
development (Choi et al. 2013, Burté et al. 2015, Denton
et al. 2018), ROS production (Yu et al. 2006, Huang et al.
2016, Ježek et al. 2018) and apoptosis (Frank et al. 2001,
Olichon et al. 2003, Suen et al. 2008).
Mitochondrial fission promotes fragmented, separated
mitochondria in a process regulated by several proteins,
including dynamin-related protein 1 (DRP1), a master
regulator of mitochondrial division in eukaryotic cells
and mitochondrial fission protein 1 (FIS1). Conversely,
mitochondrial fusion generates large, interconnected
mitochondrial
networks.
Three
dynamin-related
proteins, namely mitofusins 1 and 2 (MFN1 and MFN2),
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and optic atrophy 1 (OPA1), mediate mitochondrial fusion
in mammals (Suárez-Rivero et al. 2016, Williams & Ding
2017). Both processes contribute to keep a healthy pool of
mitochondria by actively participating in mitophagy, the
mitochondrial quality control process by which damaged
or dysfunctional mitochondria are eliminated by selective
autophagy (Lemasters 2005, Williams & Ding 2017).
The mitophagic process is mainly orchestrated by two
main proteins, namely phosphatase and tensin homolog
(PTEN)-induced putative kinase 1 (PINK1) and Parkin
(PARK2). More recently, other proteins participating
in mitophagy have been identified, including the E3
ubiquitin ligase ariadne RBR E3 ubiquitin protein ligase 1
(ARIH1) and the inner mitochondrial membrane protein,
prohibitin 2 (PHB2) (Palikaras & Tavernarakis 2014, Villa
et al. 2017, Wei et al. 2017).
ROS and oxidative stress
Mitochondria are considered the major source of
intracellular ROS, which are mainly produced as
consequence of electron leak from the ETC during the
OXPHOS. Mitochondria present at least 11 different
sites associated with ROS generation; it is generally well
accepted that complexes I and III are the two major sites
(Brand 2016).
ROS act as a double-edged sword for the cells.
Physiological concentrations of ROS act as second
messengers in diverse cellular and mitochondrial
processes and signaling pathways (Sena & Chandel 2012).
Conversely, excessive ROS can react with lipids, nucleic
acids (including mtDNA) and proteins, causing oxidative
damage and, eventually, cell death (Circu & Aw 2010). To
keep ROS levels under control and avoid their potentially
detrimental effects, mitochondria have evolved an
antioxidant defense composed by non-enzymatic (e.g.
ascorbic acid and α-tocopherol) and enzymatic (e.g.
catalase and superoxide dismutase, SOD) systems (Sies
1993). Moreover, it has been suggested that UCP2 and
UCP3 might be involved in the control of ROS production
(Arsenijevic et al. 2000, Mailloux & Harper 2011, Pons
et al. 2015). When antioxidant defenses fail to cope with
excessive ROS production, cells undergo oxidative stress,
which has been associated with IR and T2DM (Houstis
et al. 2006, Anderson et al. 2009, Tangvarasittichai 2015).
Mitochondria and cell death
Along with their role in energy production, mitochondria
are also implicated in several signaling pathways.
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For instance, mitochondria play a crucial role in
the intrinsic pathway of apoptosis, which requires
permeabilization of the outer mitochondrial membrane
(OMM). Regulation of OMM permeabilization depends
on the balance between anti- and pro-apoptotic B-cell
lymphoma 2 (BCL-2) family proteins. This family
comprises three groups of proteins: anti-apoptotic (e.g.
BCL-2 and BCL-XL), pro-apoptotic (e.g. BAX and BAK)
and BH3-only proteins (e.g. PUMA, and BIM) (Youle
& Strasser 2008). Upon exposure to cell death stimuli
(e.g. DNA damage), BH3-only proteins translocate
to mitochondria, where they bind and inactivate
anti-apoptotic BCL-2 proteins. Subsequently, BH3only proteins stimulate BAX and BAK, causing OMM
permeabilization and release of pro-apoptotic proteins,
such as cytochrome c and SMAC/DIABLO, from the
intermembrane
space.
Additionally,
long-lasting
opening of the mitochondrial permeability transition
pore (PTP) also contributes to cytochrome c release
under certain conditions (e.g. glucose deprivation and
ischemia/reperfusion injury). Once in the cytosol,
cytochrome c binds to the apoptotic protease activating
factor 1, leading to the activation of caspase-9 and -3,
and, ultimately, apoptosis (Ow et al. 2008, Youle &
Strasser 2008).
EDCs and T2D
EDCs have been defined by the Endocrine Society as ‘an
exogenous chemical, or mixture of chemicals, that can
interfere with any aspect of hormone action’ (Zoeller
et al. 2012). The definition includes a great variety of
compounds, such as industrial and waste products,
plasticizers, flame retardants, pesticides and food
additives. Human exposure mainly occurs by ingestion,
inhalation and dermal uptake (Gore et al. 2015). The
current knowledge on the relationship between EDCs and
T2D is briefly discussed below and in other comprehensive
reviews (Alonso-Magdalena et al. 2011, Gore et al. 2015,
Heindel et al. 2017, Mimoto et al. 2017, Nadal et al. 2017,
Lind & Lind 2018).
Although initial concern on EDCs was focused on
their capacity to induce reproductive abnormalities, we
have learned over the years that these compounds can
also exert other detrimental effects. In this regard, an
enlarging body of evidence has provided a strong support
for the role of EDCs in the etiology of diabetes and other
metabolic disorders (Alonso-Magdalena et al. 2011,
Gore et al. 2015, Heindel et al. 2017, Nadal et al. 2017).
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Among them, those with the most conclusive evidence of
a diabetogenic role are plasticizers like BPA and phthalates,
some persistent organic pollutants (POPs), such as dioxins,
polychlorinated biphenyls (PCBs), perfluorooctanoic
acid (PFOA) and perfluorooctane sulfonate (PFOS), and
dichlorodiphenyltrichloroethane (DDT), as well as some
heavy metals, including arsenic and cadmium (Gore et al.
2015, Cardenas et al. 2017).
Numerous studies conducted in animals have
explored the metabolic effects of MDCs at different
timing of exposure. In adult animals, several MDCs
have been shown to decrease insulin sensitivity and
promote glucose intolerance. For instance, BPA exposure
(100 μg/kg/day) resulted in postprandial hyperinsulinemia,
impaired glucose tolerance and marked IR in mice
(Alonso-Magdalena et al. 2006) along with defective
insulin signaling in liver and muscle (Batista et al. 2012).
Additionally, BPA exposure (50 μg/kg) diminished hepatic
glucokinase activity (Perreault et al. 2013). At higher
doses (20 and 200 mg/kg/day), BPA also impaired insulin
signaling and decreased hepatic glucose oxidation and
glycogen content (Jayashree et al. 2013). Analogously, the
exposure to some PCBs, such as aroclor (0.5, 5, 50 and
500μg/kg/day), PCB-118 (37.5mg/kg), PCB-138 (37.5mg/kg) or
PCB-126 (10 μg/kg/day), has been associated to increased
body weight gain, IR, hyperinsulinemia and changes in
pancreatic α- (decrease) and β-cell (increase) mass (Ruzzin
et al. 2009, Zhang et al. 2015a, Kim et al. 2016, Loiola
et al. 2016). Importantly, complex interactions between
diet and PCBs have been reported in the development
of metabolic disorders. Thus, aroclor (36 mg/kg/week)
exacerbated high-fat diet (HFD)-induced IR (Gray et al.
2013), while other PCBs (PCB-77: 50 mg/kg; PCB-126:
1.6 mg/kg) provoked glucose intolerance and impaired
insulin sensitivity in obese mice only when there
was a switch from HFD to a less caloric diet (Baker et al.
2013, 2015).
Cadmium and arsenic may also promote perturbations
on glucose handling. Cadmium administration has been
shown to promote hyperglycaemia, impaired glucose
tolerance and reduced plasma insulin levels (Ithakissios
et al. 1975, Merali & Singhal 1980, Kanter et al. 2003,
Edwards & Prozialeck 2009, Trevino et al. 2015). Similarly,
arsenic (0.05–50 ppm) has been shown to alter glucose
tolerance (Paul et al. 2011, Huang et al. 2015), an effect
that was aggravated in diabetic mice (Liu et al. 2014)
or in the presence of a metabolic stressor (e.g. HFD)
(Paul et al. 2011).
Increasing attention has been focused on the
exposure to MDCs during intrauterine life, which turns
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out to be an extremely sensitive period. Several studies
have largely demonstrated that maternal exposure to
environmental pollutants during development may lead
to severe metabolic perturbations. Thus, offspring from
mice exposed to BPA (5–5000 μg/kg/day) during pregnancy
manifested glucose intolerance, IR as well as alterations
on β-cell function and mass (Alonso-Magdalena et al.
2010, Angle et al. 2013). Impairments on glucose and
lipid metabolism were exacerbated when animals were
challenged with HFD (Wei et al. 2011, García-Arevalo et al.
2014) and, in some cases, were accompanied by alterations
in the structure of the hypothalamic energy balance
circuitry (MacKay et al. 2013, 2017). At earlier stages,
BPA (10 μg/kg/day and 25 mg/kg/diet) altered pancreas
development (Garcia-Arevalo et al. 2016, Whitehead
et al. 2016). In addition, metabolomics studies have
demonstrated global changes in metabolism, including
energy metabolism and brain function on BPA-exposed
pups (0.025, 0.25 and 25 μg/kg/day) (Cabaton et al. 2013).
Importantly, BPA-induced metabolic disorders can be
transmitted to next generation (Li et al. 2014, Susiarjo
et al. 2015, Bansal et al. 2017).
Notably, the adverse metabolic outcomes affect not
only the offspring but also the mother. BPA-exposed dams
(10 and 100 μg/kg/day) developed gestational glucose
intolerance and decreased insulin sensitivity (AlonsoMagdalena et al. 2010, Susiarjo et al. 2015). Although these
metabolic perturbations disappeared after parturition, the
remission was only temporal and alterations reappeared
months later (Alonso-Magdalena et al. 2015).
Prenatal exposure to PCB has also been linked to the
programming of glucose and energy homeostasis in the
offspring. Exposure to PCB-153 (0.09–1406 μg/kg/day)
during gestation and lactation resulted in increased glucose
levels in the male offspring while, in the female, promoted
increased glucagon levels and decreased pancreatic weight
(van Esterik et al. 2015). In combination with a HFD,
PCB exposure provoked hepatic steatosis, alterations in
the plasma adipokine profile and increased expression
of genes related to lipid biosynthesis (Wahlang et al.
2013). Likewise, DDT-exposed offspring (1.7 mg/kg/day)
manifested glucose intolerance, hyperinsulinemia,
dyslipidemia and impaired thermogenesis (La Merrill
et al. 2014).
The metabolic effects of di(2-ethylhexyl) phthalate
(DEHP) have also been explored. DEHP exposure (1.25
and 6.25 mg/kg/day) throughout gestation and lactation
resulted in abnormalities in pancreas development and
function, which were reflected by decreased pancreatic
β-cell mass and insulin content at the moment of weaning
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(Lin et al. 2011). When getting older (8–9 weeks of age),
DEHP-exposed animals presented elevated glucose levels
and impaired glucose and insulin tolerance.
Other persistent compounds, such as PFOS (16, 32
and 64 μM), have been proposed to disrupt pancreas
organogenesis (Sant et al. 2017). This has been
demonstrated to occur in zebrafish while, in rodents, PFOS
(0.3 and 3 mg/kg/day) administration during gestational
and lactational periods altered glucose metabolism not
only in the offspring but also in the mother (Wan et al.
2014). Conversely, no changes on glucose tolerance
were observed in the PFOA-offspring (3–3000 μg/kg/day),
although the animals exhibited alterations in the hepatic
structure (van Esterik et al. 2016).
Regarding human data, a number of cross-sectional
studies have established a link between BPA levels and
the incidence of T2D. Representative data from National
Health and Nutrition Examination Survey (NHANES)
(2003–2004) demonstrated a positive correlation
between BPA levels and increased incidence of T2D and
cardiovascular disease (Lang et al. 2008). Similar results
were observed in data pooled across collection years
(2003–2004/2005–2006) (Melzer et al. 2010). Studies based
on NHANES 2003–2008 reported a connection between
BPA levels and the incidence of diabetes (Shankar &
Teppala 2011) and prediabetes (Sabanayagam et al. 2013)
independently of traditional diabetes risk factors. BPA has
also been linked to the prevalence of IR, hyperinsulinemia
and adverse glucose homeostasis (Wang et al. 2012,
Beydoun et al. 2014, Tai & Chen 2016). In children, BPA
has been associated to the presence of IR regardless of BMI
(Menale et al. 2017). Human exposure to some phthalate
metabolites has also been associated with elevated
fasting glucose and insulin levels, IR, as well as increased
prevalence of diabetes in different populations (Svensson
et al. 2011, James-Todd et al. 2012, Lind et al. 2012, Kim
et al. 2013, Trasande et al. 2013, Huang et al. 2014, Sun
et al. 2014a, Dales et al. 2018).
Besides that, a large number of epidemiological
evidence supports the role of different POPs in metabolic
disorders. This is the case of some PCBs and organochlorine
pesticides that have been correlated with decreased
insulin sensitivity and diabetes risk (Wang et al. 2008,
Lee et al. 2010, 2011, Wu et al. 2013, Suarez-Lopez et al.
2015). Some studies have also evaluated the metabolic
consequences of POP exposure in early life. Thus, prenatal
exposure to some PCBs has been associated with increased
fasting insulin levels in girls at 5 years of age (TangPeronard et al. 2015), while PCBs and organochlorine
exposure has been related to decreased insulin levels
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in newborns (Debost-Legrand et al. 2016). Regarding
perfluorinated compounds (PFCs), PFOA exposure has
been linked to elevated diabetes prevalence in adults
(He et al. 2017) and elderly (Lind et al. 2014), while an
association between PFOA levels and impaired β-cell
function has been observed in adulthood (Domazet
et al. 2016). Perfluoroalkoxy alkanes exposure during
pregnancy was positively related to impaired gestational
glucose tolerance (Matilla-Santander et al. 2017).
Mitochondria and T2D
Numerous studies have reported mitochondrial alterations
in peripheral tissues that play a crucial role in the control
of glucose metabolism (Kelley et al. 2002, Kusminski &
Scherer 2012, Sebastian et al. 2012, Supale et al. 2012).
However, whether those abnormalities are the cause or
a consequence of T2D remains unclear. As this subject is
outside the scope of the present review, and it has been
extensively reviewed elsewhere, the interested reader is
referred to some reviews on the topic (Patti & Corvera
2010, Szendroedi et al. 2011, Di Meo et al. 2017, GonzalezFranquesa & Patti 2017, Fex et al. 2018).
MDCs and mitochondria
Effects of MDCs on mitochondria have been described
since the 1960s. Yet up to date, only a few studies have
shown a correlation between MDC-induced mitochondrial
dysfunction and IR/T2D. In this section, we discuss those
mechanisms.
MDCs and mitochondrial bioenergetics
Numerous studies have reported that MDCs exposure
affect mitochondrial bioenergetics, either via direct
interaction with mitochondrial proteins or secondary to
transcriptional changes (Melnick & Schiller 1982, Moreno
& Madeira 1991, Shertzer et al. 2006, Walters et al. 2009,
Carchia et al. 2015).
In pancreatic islets, BPA (25 μg/L) induced
mitochondrial swelling and decreased cytochrome
c oxidase activity and ATP levels (Song et al. 2012).
This reduction in ATP levels was later confirmed in rat
INS-1E cells, and it was associated with a BPA-induced
reduction in mitochondrial mass, dissipation of
the mitochondrial membrane potential (MMP) and
abnormal expression of genes involved in mitochondrial
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function (Lin et al. 2013). To better understand the
mechanisms whereby environmental doses of BPA lead to
mitochondrial dysfunction in isolated islets, Carchia and
colleagues used a transcriptomic approach, which revealed
that 1 nM BPA decreased the expression of 29 genes,
some of which were involved in OXPHOS and
mitochondrial dysfunction, such as Uqcrb, Atp1b1 and Iars
(Carchia et al. 2015). Interestingly, these findings were not
restricted to ex vivo or in vitro studies. Pancreatic islets from
F1 and F2 adult male mice offspring of mothers exposed
to BPA (10 mg/kg/day) presented impaired mitochondrial
oxygen consumption and changes in the expression
of several mitochondrial genes (Bansal et al. 2017). As
mitochondria are critical for the regulation of β-cell
mass and function (Kaufman et al. 2015), mitochondrial
dysfunction might be related to BPA-induced β-cell
impairment (Alonso-Magdalena et al. 2006, Carchia et al.
2015, Bansal et al. 2017).
Upregulation of Ucp2 mRNA expression has been
found upon BPA exposure (Wei et al. 2011, Song et al.
2012, Bansal et al. 2017). Elevated UCP2 activity might
be, at least in part, responsible for the above-mentioned
reduction in the MMP and ATP levels, leading to attenuated
GSIS, as reported in islets from UCP2-overexpressing
animals (Chan et al. 1999, 2001). However, it is important
to confirm UCP2 expression at protein level before
drawing any conclusion, as it has been shown that UCP2
expression is mainly regulated at the translational level
(Hurtaud et al. 2007).
Multiple cellular processes could be potentially
affected by mitochondrial dysfunction in hepatocytes.
Augmented hepatic lipid accumulation has been found
in adult rats treated with atrazine (30 μg/kg/day) (Lim
et al. 2009), BPA (40 μg/kg/day) (Jiang et al. 2014a) and
tributyltin (0.1 μg/kg/day) (Bertuloso et al. 2015) and was
usually accompanied by reduced activity of mitochondrial
proteins (mainly respiratory complexes I and III), MMP
and ATP production (Lim et al. 2009, Jiang et al. 2014a).
Studies in hepatocyte cell lines and/or mitochondria
isolated from liver suggest that these effects may be direct
on mitochondria (Nakagawa & Tayama 2000, Gogvadze
et al. 2002, Lim et al. 2009, Huc et al. 2012, Moon et al.
2012, Sagarkar et al. 2016). Altogether, these studies
suggest that intrahepatic lipid accumulation derived from
mitochondrial dysfunction might be partially responsible
for the IR and glucose intolerance observed in atrazine- and
BPA-treated animals (Lim et al. 2009, Alonso-Magdalena
et al. 2010, Wei et al. 2011, García-Arevalo et al. 2014).
Atrazine exposure also leads to muscle lipid
accumulation, reduced mitochondrial respiration and
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changes in mitochondrial morphology. Curiously, reduced
oxygen consumption rate was not related to changes in
the protein expression of several mitochondrial OXPHOS
complex subunits (e.g. SDHA and UQCRC2), but rather
to direct effects on mitochondrial complex III. Moreover,
atrazine-treated rats were insulin resistant and presented
low energy expenditure (Lim et al. 2009). In L6 myotubes,
atrazine treatment (50 and 100 μM) resulted in the
downregulation of several genes related to OXPHOS (e.g.
mt-Co3 and Sdhc) and mitochondrial biogenesis (e.g. Tfam),
leading to reduced ATP production (Sagarkar et al. 2016).
Similar results were observed in cardiac muscle from BPAtreated male rats (50 μg/kg/day). Additionally, BPA-treated
animals also presented reduced MMP and activities of
mitochondrial complexes I–IV (Jiang et al. 2015). Similarly,
prenatal exposure to BPA (50 μg/kg/day) downregulated
genes related to OXPHOS pathway (e.g. Cycs), fatty
acid oxidation (e.g. Acadm and Lp1) and mitochondrial
biogenesis (e.g. Nrf1 and Ppargc1a) as well as reduced MMP
in heart of neonatal rats (Jiang et al. 2014b). TCDD (10 nM)
induced mitochondrial dysfunction in C2C12 skeletal
myoblasts, leading to dissipation of MMP, reduced levels
of mitochondrial genome-coded cytochrome c oxidase
subunits I and II and increased ROS production (Biswas
et al. 2008). Despite the lack of more direct evidence on
IR and T2D development, the results above are in line
with findings in insulin-resistant and/or T2D individuals,
in which alterations in muscle mitochondrial capacity
and gene expression (e.g. NRF1, SDHC and PPARGC1A),
as well as increased intramyocellular lipid accumulation,
have been documented (Jacob et al. 1999, Patti et al. 2003,
Petersen et al. 2004).
In human adipose-derived stem cells, tributyltin
(100 nM) inhibited oxygen consumption (Llobet et al.
2015). Similarly, 3T3-L1 adipocytes exposed to BPA
(10 nM), 4-nonylphenol (600 pM) and diethylstilbestrol
(0.23 pM) exhibited decreased mitochondrial respiration
and mitochondria-associated ATP production, as well
as reduced glycolytic function (Tsou et al. 2017). These
effects might be due to direct effects on the activity
of mitochondrial proteins and/or modulation of
mitochondria biogenesis, which are consistent with the
mitochondrial impairment observed in WAT from obese/
T2D individuals (Bogacka et al. 2005, Choo et al. 2006,
Dahlman et al. 2006, Rong et al. 2007).
MDCs and mitochondrial biogenesis
A wide variety of MDCs interfere with mitochondrial
biogenesis by modulation of proteins involved in this
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process. For instance, livers from rats exposed to sodium
arsenite (25 ppm) presented reduced levels of Nrf1,
Nrf2 and Tfam, and Ppargc1a (PGC-1α) and diminished
expression and activity of mitochondrial complexes
(Prakash & Kumar 2016). In human liver HepG2 cells and
C3H10T1/2 mesenchymal stem cells, the plasticizer benzyl
butyl phthalate (BBP, 1 nM–50 μM) also downregulated
the expression of NRF1, NRF2, TFAM and PPARGC1A
(Zhang et al. 2015b, Zhang & Choudhury 2017).
Additionally, levels of sirtuins (SIRT) 1 and 3, two NAD+dependent deacetylases with different roles in the control
of mitochondrial biogenesis (Nogueiras et al. 2012), were
also decreased. Under certain metabolic conditions (e.g.
fasting or obesity), SIRT1 and SIRT3 can also impact hepatic
gluconeogenesis and fatty acid metabolism (Milne et al.
2007, Hirschey et al. 2010), pancreatic insulin secretion
and viability (Moynihan et al. 2005, Caton et al. 2013)
and fatty acid and glucose metabolism in skeletal muscle
and adipose tissue (Picard et al. 2004, Jing et al. 2011).
Hence, downregulation of these proteins may impair
metabolic function, leading to metabolic diseases. In fact,
some studies have shown that Sirt1 deletion results in
hyperglycaemia and IR (Wang et al. 2011), whereas SIRT1
gain-of-function prevents diabetes in mice models (Banks
et al. 2008). Similarly, Sirt3-knockout mice and cultured
myoblasts silenced for Sirt3 exhibited increased oxidative
stress and impaired insulin signaling (Jing et al. 2011).
Reportedly, hearts from neonatal rats prenatally
exposed to BPA (50 μg/kg/day) had decreased expression of
mitochondrial biogenesis regulators (PGC-1α, ERRα, ERRγ,
PPARα, NRF1 and TFAM) (Jiang et al. 2014b). Likewise,
long-term exposure to BPA (50 μg/kg/day) induced PGC-1α
promoter hypermethylation and reduced Ppargc1a
expression in heart tissue upon 24 and 48 weeks of
treatment (Jiang et al. 2015). Interestingly, similar results
were found in skeletal muscle from insulin-resistant
patients with T2D and obese individuals, where PGC-1α
methylation was related to reduced mitochondrial
biogenesis (Barrès et al. 2009, 2013). Along with decreased
PGC-1α expression, BPA-treated animals also displayed
reduced levels of Nrf1, Nrf2 and Tfam, and some of
their target genes, including Atp5e, Atp5o, Uqcrc2 and
Uqcrf1. These data show that BPA-induced perturbations
in mitochondrial biogenesis might be, at least partially,
responsible for the mitochondrial abnormalities observed
in BPA-treated animals, such as reduction in the activity of
mitochondrial proteins, depolarized MMP and decreased
ATP levels (Lin et al. 2013, Jiang et al. 2014b, 2015).
Another mechanism by which MDCs may induce
mitochondrial perturbations was described in human
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trophoblast-like JAR cells treated with 2 nM TCDD (Chen
et al. 2010). In this study, TCDD exposure decreased
mtDNA copy number and increased mtDNA deletions,
including a 7599-bp deletion of mtDNA encompassing
genes encoding proteins involved in mitochondrial
function. In addition, TCDD cells presented reduced
MMP, lower ATP levels and increased oxidative stress.
As alterations in the process of mitochondrial
biogenesis seem to be involved in the mitochondrial
dysfunction observed in insulin-responsive tissues in
T2D (Gonzalez-Franquesa & Patti 2017), changes in
mitochondrial biogenesis also seem to contribute to
EDC-induced IR.
MDCs and mitochondrial dynamics
A growing body of evidence suggests that impairment
of mitochondrial dynamics is related to IR and T2D
(Yoon et al. 2011, Rovira-Llopis et al. 2017). Alterations
in mitochondrial fission and fusion contribute to
mitochondrial dysfunction (Bach et al. 2003, Jheng et al.
2012, Boutant et al. 2017), oxidative and/or ER stress (Yu
et al. 2006, Sebastian et al. 2012, Wang et al. 2015) and
β-cell apoptosis (Men et al. 2009, Molina et al. 2009), which,
eventually, might lead to impaired glucose homeostasis
and IR. In human-induced pluripotent stem cells, exposure
to tributyltin (50 nM) or chlorpyrifos (30 μM) reduced
MFN1 expression, leading to mitochondrial fragmentation
(Yamada et al. 2016, 2017). Chlorpyrifos (25–100 μM) also
caused mitochondrial dysfunction (reduced complex I
activity, MMP and ATP levels), increased ROS production
and activation of PINK1/Parkin-mediated mitophagy
in SH-SHY5Y neuroblastoma cells (Dai et al. 2015, Park
et al. 2017). These data correlate with a study showing
fragmented mitochondrial network in myocardium of
diabetic patients, which was associated with a reduced
MFN1 expression in atrial tissue. Additionally, attenuated
complex I activity and higher ROS levels were also observed
in their atrial myocardium (Montaigne et al. 2014).
Cadmium exposure also changes mitochondrial
dynamics. Liver from cadmium-treated animals
(1–2 mg/kg/day) and L02 hepatocytes (12 μM) presented
excessive mitochondrial fragmentation, which preceded
mitochondrial
dysfunction.
Moreover,
cadmium
augmented DRP1 expression and its recruitment into
mitochondria. These changes in DRP1 expression and
recruitment, as well as mitochondrial fragmentation, were
associated with disturbances in Ca2+ homeostasis (Xu et al.
2013). The same group also showed that cadmium-induced
DRP1-dependent intense mitochondrial fission and
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mitophagy, causing mitochondrial loss and hepatotoxicity.
Interestingly, DRP1 inhibition reverted cadmium-induced
effects on mitochondria (Pi et al. 2013).
Acute exposure to high doses of BPA (25–100 μM)
induced mitochondrial dysfunction and loss, as well as
activation of PINK1/Parkin-dependent, AMPK-mediated
mitophagy in neuronal cells (Agarwal et al. 2015).
Similarly, chronic exposure to BPA (40 μg/kg/day in vivo;
100 μM in vitro) increased DRP1-mediated mitochondrial
fragmentation in the hippocampus of rat brains and in
neuronal stem cells. Interestingly, inhibition of DRP1
reverted BPA-induced mitochondrial dysfunction and
fragmentation (Agarwal et al. 2016). These findings are in
line with observations in differentiated myoblasts, in which
palmitate-induced mitochondrial dysfunction, fission
and impaired insulin-stimulated glucose uptake were
prevented by inhibition of DRP1 using pharmacological
and genetic approaches (Jheng et al. 2012).
Taken together, these studies suggest that MDCinduced alterations in mitochondrial dynamics might
be part of the mechanism by which mitochondrial
dysfunction and exacerbated oxidative stress lead to
IR. Conversely, it is worth noting that, in most cases,
mitophagy acts as a protective mechanism under certain
stress response circumstances (Kubli & Gustafsson 2012,
Meyer et al. 2017). Therefore, mitophagy activation in
response to MDCs might be a way to protect against
MDC-induced cell injury.
MDCs, ROS and oxidative stress
Due to their ability to impair mitochondrial bioenergetics,
it seems reasonable to assume that MDCs also modulate
ROS generation. PFCs, especially PFOA and PFOS, induce
ROS production likely as a consequence of inhibition
of mitochondrial respiratory chain (mainly complexes
I and II) (Panaretakis et al. 2001, Mashayekhi et al. 2015,
Shabalina et al. 2016). Of note, PFOA effects on ROS
production and MMP were reduced by treatment with
the antioxidant N-acetylcysteine (Panaretakis et al. 2001).
More recently, Han and collaborators have shown that
livers from rats treated with PFOS (1 or 10 mg/kg) presented
augmented ROS levels and diminished antioxidant defense
(decreased SOD and catalase activities; lower total GSH
and GSH/GSSG ratio) (Han et al. 2018). These findings are
in line with previous studies showing that HFD increased
the H2O2-emitting potential of mitochondria and induced
a shift of the cellular redox environment to a more
oxidized state in skeletal muscle (Anderson et al. 2009).
Interestingly, PFOS-induced oxidative stress was associated
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with activation of nuclear factor-κB (NF-κB) and tumor
necrosis factor-α (TNFα), two pathways implicated in IR
(Hotamisligil et al. 1993, Hotamisligil 1999, Arkan et al.
2005, Cai et al. 2005).
Chronic exposure to arsenic affects insulin sensitivity
in peripheral tissues through multiple mechanisms
and signaling pathways (Diaz-Villasenor et al. 2007).
A recent study showed that arsenic-induced oxidative
stress dampened insulin-dependent glucose uptake
and GLUT4 expression in adipocytes and myotubes. In
this study, arsenic treatment (0.5–2 µM) downregulated
the expression of the mitochondrial oxidative stress
response protein SIRT3 and, some SIRT3-target proteins,
namely FOXO3a, MnSOD and PGC-1α (Divya et al. 2015).
Furthermore, overexpression of SIRT3 or MnSOD partially
restored insulin sensitivity in these cells. Curiously,
SIRT3 deficiency leads to pronounced oxidative stress
and development of IR and metabolic syndrome in mice
(Hirschey et al. 2011, Jing et al. 2011).
ROS play a critical role in pancreatic β-cell dysfunction
and death (Evans et al. 2003). In general, MDC-induced
ROS contributes to β-cell death. In INS-1E cells, BPA
(25–100 μM) increased ROS production and depleted
intracellular GSH, which was followed by DNA damage
and p53 activation (Xin et al. 2014). At 1 nM, BPA-treated
islets showed increased ROS levels as well as reduced
expression of two ROS-scavenging genes, glutathione
peroxidase 3 (Gpx3) and superoxide dismutase 2 (Sod2),
resulting in NF-κB activation (Carchia et al. 2015). In both
studies, treatment with N-acetylcysteine partially rescued
BPA-induced changes, reinforcing that oxidative stress is
part of the mechanism underlying BPA effects on β-cells.
As aforementioned, BPA exposure increases Ucp2
expression in β-cells. As UCP2 activation protects β-cells
from ROS deleterious effects (Chan et al. 2004), this
increment might be a defensive response against BPAinduced β-cell stress. However, there is no evidence
supporting this statement yet.
MDCs and cell death
A common feature of T2D development is the reduction
in β-cell mass secondary to increased rates of β-cell death.
In this context, exposure to certain metabolic conditions
(e.g. chronic hyperglycemia and hyperlipidemia) activates
several stress responses that trigger β-cell apoptosis (Cnop
et al. 2005, Rhodes 2005). Likewise, many MDCs cause
β-cell apoptosis via activation of responsive mechanisms
known to be associated with β-cell demise in T2D, such as
ER and oxidative stress (Lu et al. 2011, Chang et al. 2013,
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Lin et al. 2013, Sun et al. 2014b, Carchia et al. 2015, Suh
et al. 2017a,b). For instance, INS-1 cells exposed to DEHP
(25–625 μM) presented excessive ROS generation as well
as inhibited nuclear factor erythroid 2-related factor 2
(NRF-2)-dependent antioxidant response. Furthermore,
DEHP treatment induced Ca2+ depletion and activation of
ER stress response via PKR-like ER kinase (PERK) pathway.
Ultimately, DEHP-induced persistent oxidative and ER stress
caused β-cell dysfunction and apoptosis (Sun et al. 2014b).
In response to oxidative and ER stress, several mitogenactivated protein kinases (MAPK) involved in cell survival
responses are activated (McCubrey et al. 2006, Darling &
Cook 2014). In β-cells, exposure to arsenic, cadmium or
tributyltin resulted in the activation of some MAPK, namely
c-Jun N-terminal kinase 1/2 (JNK1/2), extracellular signalregulated kinases 1/2 (ERK1/2) and p38 (Lu et al. 2011,
Chang et al. 2013, Huang et al. 2018). Interestingly, only JNK
signaling was directly implicated in apoptosis, which is in
agreement with findings suggesting a pro-apoptotic role for
JNK1 in β-cells (Marroquí et al. 2014, Dos Santos et al. 2017).
Several MDCs regulate PTP opening and expression
of BCL-2 proteins (Panaretakis et al. 2001, Gogvadze
et al. 2002, Yang et al. 2012, Xia et al. 2014), though little
is known about PTP contribution to β-cell apoptosis.
Regarding the modulation of BCL-2 members, available
studies show decreased Bcl2 expression, and either
increased (Lin et al. 2013, Carchia et al. 2015) or unchanged
(Lu et al. 2011, Chang et al. 2013) Bax expression. These
changes potentiated the BAX/BCL-2 ratio, favoring the
pro-apoptotic pathway.
Altogether, some possible mechanisms for MDCinduced, oxidative and ER stress-mediated β-cell apoptosis
include (1) induction of the transcription factor C/EBP
homologous protein (CHOP), which modulates the
expression of some BCL-2 members, such as BCL-2,
PUMA and BIM (McCullough et al. 2001, Wali et al. 2014);
(2) JNK1 activation, which activates BAX and BIM by
phosphorylation (Kim et al. 2006, Marroquí et al. 2014),
upregulates DP5 and PUMA (Gurzov et al. 2009, Cunha
et al. 2016) and downregulates MCL-1 (Allagnat et al.
2011), and (3) activation of proinflammatory pathways,
such as NF-κB and TNFα, which, among other effects,
modulate the expression of BCL-2 members (Cnop et al.
2005, Gurzov & Eizirik 2011).
Concluding remarks
Besides the great number of studies comprising MDCs
and mitochondria, little is known about the relationship
between MDC-induced mitochondria dysfunction and
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Figure 2
Metabolism-disrupting chemicals-induced
mitochondrial dysfunction may lead to insulin
resistance and type 2 diabetes. Metabolismdisrupting chemicals (MDCs) can directly or
indirectly alter several mitochondrial processes,
such as bioenergetics, biogenesis, dynamics and
ROS production. As a result, MDC-induced
mitochondrial dysfunction may disrupt insulin
sensitivity in skeletal muscle, adipose tissue and
liver, as well as induce β-cell dysfunction and cell
death. Ultimately, these effects may contribute to
the mechanism leading to insulin resistance and
type 2 diabetes.
IR/T2D, especially in tissues such as skeletal muscle and
adipose tissue. In this review, we have summarized some
of the effects promoted by MDCs on mitochondria.
Essentially, MDC-induced mitochondrial dysfunction
is characterized by perturbations in mitochondrial
bioenergetics, biogenesis and dynamics, excessive ROS
production and activation of the mitochondrial pathway
of apoptosis. These alterations might be relevant for
insulin-responsive tissues, in which emerging evidence
implicate mitochondrial dysfunction as a contributor
mechanism linking MDCs to T2D development (Di Meo
et al. 2017, Fex et al. 2018). Furthermore, it is important
to keep in mind that humans are exposed to a mixture
of MDCs that might affect mitochondrial function
and metabolic homeostasis simultaneously, leading to
alterations in insulin sensitivity (adipose tissue, skeletal
muscle and liver) as well as cell dysfunction and death
(pancreatic β-cells) (Fig. 2).
Recent advances in the field of omics will be of great
advantage for MDC research. For instance, the use of
mitochondriomics technology, which is the study of the
properties of mitochondrial DNA, has been suggested
to identify molecular ‘fingerprints’ in MDC research
(Messerlian et al. 2017). Application of mitochondriomics
along with other omics technologies (e.g. genomics,
transcriptomics and epigenomics), and integration with
more classical approaches will certainly strengthen our
knowledge of MDC exposome. Nevertheless, we believe
it is still too soon to tell whether all these omics-based
information will allow us to know if interactions between
exposome and genomics will predict a T2D phenotype.
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Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of this review.
Funding
Ministerio de Economia y Competitividad, Agencia Estatal de Investigación
(AEI) and Fondo Europeo de Desarrollo Regional (FEDER), EU grants
BPU2017-86579-R and SAF2014-58335-P (A N) and BFU2016-77125-R
(I Q) and Generalitat Valenciana PROMETEO II/2015/016. L M holds a
Juan de la Cierva fellowship from the Ministry of Economy, Industry
and Competitiveness (IJCI-2015-24482). CIBERDEM is an initiative of the
Instituto de Salud Carlos III.
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Received in final form 26 July 2018
Accepted 1 August 2018
Accepted Preprint published online 2 August 2018
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