![Bisphenol A](https://upload.wikimedia.org/wikipedia/commons/e/ee/Bisphenol_A.svg)
Obesogens are foreign
chemical compound
A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...
s that are hypothesised to disrupt normal
development
Development or developing may refer to:
Arts
*Development hell, when a project is stuck in development
*Filmmaking, development phase, including finance and budgeting
*Development (music), the process thematic material is reshaped
* Photograph ...
and balance of
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
, which in some cases, can lead to
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
.
Obesogens may be functionally defined as chemicals that inappropriately alter lipid
homeostasis
In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of
appetite and
satiety to promote fat accumulation and
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
.
There are many different proposed mechanisms through which obesogens can interfere with the body's
adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...
biology. These mechanisms include alterations in the action of metabolic sensors; dysregulation of
sex steroid synthesis, action or breakdown; changes in the central integration of energy balance including the regulation of appetite and satiety; and reprogramming of metabolic setpoints.
Some of these proposed pathways include inappropriate modulation of
nuclear receptor function which therefore allows the compounds to be classified as
endocrine disrupting chemicals that act to mimic hormones in the body, altering the normal homeostasis maintained by the endocrine system.
Obesogens have been detected in the body both as a result of intentional administration of obesogenic chemicals in the form of
pharmaceutical drugs
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...
such as
diethylstilbestrol
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
,
selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
s, and
thiazolidinedione
The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used i ...
and as a result of unintentional exposure to environmental obesogens such as
tributyltin
Tributyltin (TBT) is an umbrella term for a class of organotin compounds which contain the (C4H9)3 Sn group, with a prominent example being tributyltin oxide. For 40 years TBT was used as a biocide in anti-fouling paint, commonly known as bo ...
, bisphenol A,
diethylhexylphthalate, and
perfluorooctanoate.
The term obesogen was coined in 2006 by Felix Grün and Bruce Blumberg of the
University of California, Irvine
The University of California, Irvine (UCI or UC Irvine) is a public land-grant research university in Irvine, California. One of the ten campuses of the University of California system, UCI offers 87 undergraduate degrees and 129 graduate and p ...
.
The topic of this proposed class of chemical compounds and how to counteract their effects is explored at length in the book ''
The New American Diet''.
Mechanisms of action
There are many ways in which obesogenic drugs and chemicals can disrupt the body's adipose tissue biology. The three main mechanisms of action include
* alterations in the action of metabolic sensors in which obesogens mimic metabolic
ligands acting to either block or upregulate
hormone receptors
A hormone receptor is a receptor molecule that binds to a specific chemical messenger . Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptor ...
* dysregulation of sex steroid synthesis, in which they alter the ratio of sex hormones leading to changes in their control of lipid balance
* changes in the central integration of
energy balance Energy balance may refer to:
* Earth's energy balance, the relationship between incoming solar radiation, outgoing radiation of all types, and global temperature change.
* Energy accounting, a system used within industry, where measuring and anal ...
including the regulation of appetite and satiety in the brain and the reprogramming of metabolic setpoints.
Metabolic sensors
Obesogenic drugs and chemicals have been shown to target transcription regulators found in gene networks that function to control
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
lipid homeostasis and proliferation and differentiation on adipocytes. The major group of regulators that is targeted is a group of nuclear hormone receptors known as
peroxisome proliferator activated receptors (PPARα, δ, and γ). These hormone receptors sense a variety of metabolic ligands including lipophilic hormones, dietary fatty acids and their metabolites, and, depending on the varying levels of these ligands, control transcription of genes involved in balancing the changes in lipid balance in the body.
To become active and properly function as metabolic sensors and transcription regulators, the PPAR receptors must
heterodimerize with another receptor known as the 9-cis
retinoic acid receptor
The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid the retinoid active derivatives of Vitamin A ...
(RXR). The RXR receptor itself is the second major target of obesogens next to the PPAR receptors.
The PPARα receptor, when complexed with RXR and activated by the binding of a lipid, promotes
peroxisome proliferation leading to increased fatty acid β-oxidation.
Substances, such a
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
that target and act as agonists of PPARα, typically act to reduce overall serum concentrations of lipids. In contrast, the PPARγ receptor, when complexed with RXR and activated by the binding of fatty acids or their derivatives, promotes lipid biosynthesis and storage of lipids is favored over fatty acid oxidation. In addition, activation promotes differentiation of
preadipocytes
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. ...
and the conversion of mesenchymal
progenitor cells
In genealogy, the progenitor (rarer: primogenitor; german: Stammvater or ''Ahnherr'') is the – sometimes legendary – founder of a family, line of descent, clan or tribe, noble house, or ethnic group..
Ebenda''Ahnherr:''"Stammvater eines G ...
to preadipocytes in adipose tissues. Substances that target and act as agonists of PPARγ/RXR complex typically act to increase overall serum concentrations of lipids.
Obesogens that target the PPARγ/RXR complex mimic the metabolic ligands and activate the receptor leading to upregulation of lipid accumulation which explains their obesogenic effects. However, in the case of obesogens that target the PPARα/RXR complex, which when stimulated reduces adipose mass and body weight, there are a few explanations as to how they promote obesity.
The ligand binding pockets of PPARs are very large and unspecified, allowing for different
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
of the receptor (PPARα, δ, and γ) to be activated by the same agonist ligands or their metabolites. In addition, fatty acid oxidation stimulated by
PPARα
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gen ...
requires continuous stimulation while only a single activation event of
PPARγ
Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance
receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
is required to permanently increase adipocyte differentiation and number.
Therefore, it may be the case that metabolites of PPARα targeting obesogens are also activating PPARγ, providing the single activation event needed to potentially lead to a pro-adipogenic response.
A second explanation points to specific PPARα targeters that have been shown to additionally cause abnormal transcriptional regulation of testicular
steroidogenesis
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
when introduced during fetal development. This abnormal regulation leads to a decreased level of
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
in the body which, itself, is obesogenic.
Finally, if PPARα activation occurs during critical periods of development, the resulting decrease in lipid concentration in the developing fetus is recognized by the fetal brain as undernourishment. In this case, the developing brain makes what will become permanent changes to the body's metabolic control, leading to long-term upregulation of lipid storage and maintenance.
Sex steroid dysregulation
Sex steroids normally play a significant role in lipid balance in the body. Aided by other peptide hormones such as
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
, they act against the lipid accumulation mediated by insulin and cortisol by mobilizing lipid stores that are present. Exposure to obesogens often leads to a deficiency or change in the ratio between androgen and estrogen sex steroid levels, which modifies this method of lipid balance resulting in lowered growth hormone secretion, hypocortisolemia (low levels of circulating cortisol), and increased resistance to insulin effects.
This alteration in sex steroid levels due to obesogens can vary enormously according to both the sex of the exposed individual as well as the timing of the exposure.
If the chemicals are introduced at critical windows of development, the vulnerability of an individual to their effects is much higher than if exposure occurs later in adulthood. It has been shown that obesogenic effects are apparent in female mice exposed to both phytoestrogens and DES during their neonatal periods of development, as they, though born with a lower birth weight, almost always developed obesity, high leptin levels, and altered glucose response pathways.
Both phytoestrogen and DES exposed male mice did not develop obesity and, rather, showed decreased body weights with increased exposure confirming the role of gender differences in exposure response.
Further studies have shown positive correlations for serum BPA levels with obese females in the human population, along with other xenoestrogen compounds suggesting the parallel roles that these effects may be having on humans.
Central balance of energy
While hormone receptors tend to be the most obvious candidates for targets of obesogens, central mechanisms that balance and regulate the body's nutritional changes on a day-to-day basis as a whole cannot be overlooked. The
HPA axis HPA may refer to:
Organizations
* Harry Potter Alliance, a charity
* Halifax Port Authority, Canada
* Hamburg Port Authority, Germany
* Hawaii Preparatory Academy, a school in Hawaii, US
* Health Protection Agency, UK
* Heerespersonalamt, the Ger ...
(hypothalamic-pituitary-adrenal) is involved in controlling appetite and energy homeostasis circuits which are mediated by a large number of monoaminoergic, peptidergic (use of hormones as neurotransmitters), and
endocannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
signals that come from the digestive tract, adipose tissues, and from within the brain. It is these types of signals that provide a likely target for obesogens that have shown to have weight altering effects.
Neuroendocrine effects
Neurological disorders may enhance the susceptibility to develop the
metabolic syndrome that includes obesity.
Many neuropharmaceuticals used to alter behavioral pathways in patients with neurological disorders have shown to have metabolic altering side-effects leading to obesogenic phenotypes as well. These findings give evidence to conclude that an increase in lipid accumulation can result from the targeting of neurotransmitter receptors by foreign chemicals.
[See also: #Central integration of energy balance]
Peptidergic hormones
Several peptidergic hormone pathways controlling appetite and energy balance —such as those involving
ghrelin
Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are hi ...
,
neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...
, and
agouti-related peptide
Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nu ...
— are particularly sensitive to changes in nuclear receptor signaling pathways and can therefore be easily altered by the introduction of
endocrine disruptors. Such an alteration can lead to induced feelings of hunger and decreased feelings of fullness causing an increase in food intake and inability to feel satisfied, both characteristic of obesity.
Some xenoestrogens such as
BPA,
nonylphenol
Nonylphenols are a family of closely related organic compounds composed of phenol bearing a 9 carbon-tail. Nonylphenols can come in numerous structures, all of which may be considered alkylphenols. They are used in manufacturing antioxidants, lubr ...
, and
DEHP
Bis(2-ethylhexyl) phthalate (di-2-ethylhexyl phthalate, diethylhexyl phthalate, diisooctyl phthalate, DEHP; incorrectly — dioctyl phthalate, DIOP) is an organic compound with the formula C6H4(CO2C8H17)2. DEHP is the most common member of the cl ...
have all shown to act is this way, altering
NPY expression and significantly shifting the feeding behaviors of exposed mice.
In addition,
organotins such as trimethyltin (TMT), triethyltin (TET), and
tributyltin
Tributyltin (TBT) is an umbrella term for a class of organotin compounds which contain the (C4H9)3 Sn group, with a prominent example being tributyltin oxide. For 40 years TBT was used as a biocide in anti-fouling paint, commonly known as bo ...
(TBT) compounds can exert their effects through similar pathways. TBT can locally disrupt
aromatase
Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...
regulation in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
causing the responses of the HPA axis to hormones to become abnormal. TMT works in a similar but unique way, inducing NPY and NPY2 receptor expression initially which later is counteracted by neuronal degeneration in lesions causing decrease in signaling ability.
While an increase in food intake is often the case after exposure, weight gain involves the body's maintenance of its metabolic setpoint as well. Given this information, it is particularly important to note that exposure during development and initial programming of these setpoints can be extremely significant throughout the remainder of life.
Endocannabinoid signaling
A wide range of environmental organotins that mimic petidergic hormones in the HPA axis as mentioned before, additionally mimic lipid activators of the
cannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
system and inhibit
AMPK AMPK may refer to:
* AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...
activity.
Endocannaboid levels are high in those suffering from obesity due to hyperactivity of cannaboid signalling pathways. It is these high levels that have been found to be closely associated with increased fat stores linking the lipid activator mimics to the actual disease.
Programming of metabolic set points
Regions in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
control the responses that establish an individuals metabolic setpoint and metabolic efficiency. These responses are adaptive in that they vary according to the individual's needs, always working to restore the metabolic setpoint through the increase or decrease of metabolic functions depending on varying energy needs. Since it is adapted, it is expected that it would be able to achieve equilibrium if the lipid balance was altered by hormones via the mechanisms mentioned above. However, since obesogenic phenotypes persist, it can be concluded that adaptive response components of the hypothalamus may be a target of obesogens as well.
A person's body composition is very much predetermined before birth and changes rarely occur in adulthood. Adipocyte numbers increase during development and come to a plateau over time. After the plateau adipocytes become restricted to mostly
hypertrophic
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...
growth and don't seem to change much in terms of cell number. This is demonstrated by the difficulty in altering
somatotypes or more simply by the difficulty that goes along with trying to lose weight past a certain point.
A particular study on
polybrominated diphenyl ethers
Polybrominated diphenyl ethers or PBDEs, are a class of organobromine compounds that are used as flame retardants. Like other brominated flame retardants, PBDEs have been used in a wide array of products, including building materials, electronics, ...
(PBDE), a commonly used chemical in flame retardants, made its role in altering the functions of the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
hormone axis apparent.
This finding leads to increased concern as neonatal thyroid status plays a large role in the integration of maternal environmental signals during development in the womb that is used for long-term body weight programming.
Pharmaceutical obesogens
Obesogens detection in the body and resulting obesogenic effects can result as side effects from intentional administration of obesogenic chemicals in the form of pharmaceutical drugs. These pharmaceutical obesogens can show their effects through a variety of targets.
Metabolic sensors
Thiazolidinediones
The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in ...
(TZD),
rosiglitazone
Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutica ...
, and
pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
are all used to treat
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
. These drugs act as agonists of the PPAR-γ receptor leading to
insulin sensitizing effects that can improve
glycemic
The glycemic response to a food or meal is the effect that food or meal has on blood sugar (glucose) levels after consumption.Sadler M. Food, Glycaemic Response and Health. ILSI Europe Concise Monograph Series 2011:1-30Available from ILSI Europe ...
control and serum
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other ...
levels.
Despite the positive effects these chemicals can have in treating diabetes patients, administration also lead to unwanted PPAR-γ mediated side effects such as peripheral
edema which can be followed by persistent weight gain if the drug is used over a long period of time. These side effects are particularly prominent in diabetes 2 patients, a disease that tends to result from an overabundance of adipose tissue.
Sex steroid dysregulation
Diethylstilbestrol
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
(DES) is a synthetic estrogen that was once prescribed to women to decrease the risk of miscarriage until it was found to be causing abnormalities in exposed offspring. This same chemical has been shown to cause weight gain in female mice when exposed during neonatal development. While exposure didn't lead to an abnormal birth weight, significant weight gain occurred much later in adulthood.
Central integration of energy balance
Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
(SSRI) (e.g.
paroxetine
Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
),
tricyclic antidepressants
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
(e.g.
amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...
),
tetracyclic antidepressants (e.g.
mirtazapine
Mirtazapine, sold under the brand name Remeron amongst others, is an Atypical antidepressant, atypical antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks, but can also man ...
) and atypical
antipsychotics
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...
(e.g.
clozapine
Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...
) are all neuropharmaceuticals that target neurotransmitter receptors that are involved with brain circuits that regulate behavior. Often the function of these receptors overlaps with metabolism regulation, such as that of the
H1 receptor
The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the h ...
which when activated decreases AMPK activity.
As a result, the administration of these drugs can have side effects including increased lipid accumulation that can result in obesity.
Metabolic setpoints
The mechanisms behind SSRI, tricyclic antidepressants, and atypical antipsychotics function allow them all to have potential roles in the alteration of metabolic setpoints. TZD, in particular has been linked to regulatory function in the HPT axis, however, no conclusive evidence has been determined thus far and further research is required to confirm these hypotheses.
Environmental obesogens
While obesogens can be introduced to the body intentionally via administration of obesogenic pharmaceuticals, exposure can also occur through chemical exposure to obesogens found in the environment such as organotins and xenobiotics.
Organotins
Particular members of the organotin class of
persistent organic pollutants
Persistent organic pollutants (POPs), sometimes known as "forever chemicals", are organic compounds that are resistant to environmental degradation through chemical, biological, and photolytic processes. They are toxic chemicals that adversel ...
(POPs), namely
tributyltin
Tributyltin (TBT) is an umbrella term for a class of organotin compounds which contain the (C4H9)3 Sn group, with a prominent example being tributyltin oxide. For 40 years TBT was used as a biocide in anti-fouling paint, commonly known as bo ...
(TBT) and
triphenyltin (TPT) are highly selective and act as very potent agonists of both the retinoid X receptors (RXR α,β, and γ) and PPARγ.
This ability to target both receptors at the same time, is more effective than single receptor activation, as adopogenic signaling can be mediated through both components of the heterodimer complex. This highly effective activation mechanism can pose detrimental, long-term adipogenic effects especially if exposure occurs during development and early life.
Organotins (tin-based chemicals), used in marine anti-fouling paints, wood catalysts, plasticizers,
slimicide
Slimicide (or antislime agent) is a broad-spectrum antimicrobial pesticide used to kill slime-producing microorganisms such as algae, bacteria, fungi, and slime molds. One primary application domain is in the papermaking industry, where it reduc ...
s, in industrial water systems, and fungicides on food have recently been linked to obesogenic properties when introduced in the body.
Human exposure to these major environmental sources most commonly occurs through ingestion of contaminated seafood, agricultural products, and drinking water as well as from exposure to leaching from plastics.
Although studies that have directly measured organotin levels in human tissue and blood are limited, it has been determined that vulnerability of a portion of the general population to organotin exposure at levels high enough to activate RXRs and PPARγ receptors is very probable. The high usage of organotins in both plastics and agricultural maintenance as well as the high affinity of the chemicals further confirms this conclusion.
Liver samples from the late 1990s in Europe and Asia contained on average 6 and 84 ng/g wet wt respectively for total organotin levels, while later studies found levels of total organotins in US blood samples averaged around 21 ng/mL with TBT comprising around 8 ng/mL (~ 27 nM).
Even more recent analyses of European blood samples found the predominant species to be TPT rather than TBT at 0.09 and 0.67 ng/mL (~0.5-2 nM). Only occasional trace amounts of TBT were found.
These results indicate that organtin exposure to humans, while found to be present among many different populations, can vary in terms of type of organatin and level of exposure from region to region.
Other xenobiotics
Other common
xenobiotics
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
found in the environment have been shown to have PPAR activity, posing even further threats to dysregulated metabolic balance.
BPA from
polycarbonate plastics,
phthalate
Phthalates (, ), or phthalate esters, are esters of phthalic acid. They are mainly used as plasticizers, i.e., substances added to plastics to increase their flexibility, transparency, durability, and longevity. They are used primarily to soften ...
plasticizers used to soften PVC plastics, and various perfluoroalkyll compounds (PFCs) that are widely used surfactants and surface repellents in consumer products are all potentially obesogenic when introduced in the body.
Phthalates and PFCs in particular have been found to function as agonists for one or more of the PPARs
Additionally, metabolites of DHEP such as MEHP also activate PPARγ leading to a proadipogenic response.
Public health implications
Although research on endocrine disruptors or "obesogens" is still emerging, the public health implications so far have mainly surrounded obesity, diabetes, and cardiovascular disease.
Obesity has
become a pandemic, increasing for all population groups. From 1980 to 2008, the rates of obesity have doubled for adults and
tripled for children.
In the U.S. alone, it has been estimated that almost 100 million individuals in are obese
Traditional thinking suggested that diet and exercise alone were the main contributors to obesity; however, current experimental evidence shows that obesogens might be part of the cause.
Obesity may lead to potentially debilitating chronic diseases such as diabetes, and certain environmental exposures, or obesogens, have been directly linked to Type II diabetes mellitus (T2DM).
Potential obesogens in everyday life
Obesogens can be found in many things, from water bottles to microwaveable popcorn, and from nonstick pans to shower curtains. People interact with them on a daily basis, both intentionally and unintentionally, at work, school and home. They are an unnecessary and mostly preventable potential hazard to health, which can have a large impact on how individuals gain and lose weight.
Bisphenol-A (BPA) is an industrial chemical and organic compound that has been used in the production of plastics and resins for over a half-century. It is used in products such as toys, medical devices, plastic food and beverage containers, shower curtains, dental sealants and compounds, and register receipts.
BPA has been shown to seep into food sources from containers or into the body just by handling products made from it. Certain researchers suggest that BPA actually decreases the fat cell count in the body, but at the same time increasing the size of the ones remaining; therefore, no difference in weight is shown, and an individual is even likely to gain more.
Nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
is a chemical found in tobacco products and certain insecticides. As an obesogen, nicotine mostly acts on prenatal development after
maternal smoking occurs. A strong association has been made between maternal smoking and childhood overweight/obesity, with nicotine as the single causal agent.
Arsenic
Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, ...
is a
metalloid (''i.e.'', an element with some metallic properties) found in and on most naturally occurring substances on Earth. It can be found in the soil, ground water, air, and in small concentrations in food. Arsenic has many applications such as in the production of insecticides, herbicides, pesticides and electronic devices.
The development of diabetes has been linked to arsenic exposure from drinking water and occupational contact.
Pesticides are substances used to prevent, destroy, repel or mitigate pests, and they have been used throughout all of recorded history. Some pesticides persist for short periods of time and some for long periods of time which are considered
persistent organic pollutants
Persistent organic pollutants (POPs), sometimes known as "forever chemicals", are organic compounds that are resistant to environmental degradation through chemical, biological, and photolytic processes. They are toxic chemicals that adversel ...
(POPs). Several cross-sectional studies have shown pesticides as obesogens, linking them to obesity, diabetes and other morbidities.
Some pharmaceutical drugs are also potentially obesogens. From 2005–2008, 11% of Americans aged 12 and over took antidepressant medications.
Certain antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), are potentially adding to the almost 100 million obese individuals in the U.S.
A key function of SSRI antidepressants is to regulate the serotonin reuptake transporter (SERT) which can affect food intake and lipid accumulation leading to obesity.
Organotins such as
tributyltin
Tributyltin (TBT) is an umbrella term for a class of organotin compounds which contain the (C4H9)3 Sn group, with a prominent example being tributyltin oxide. For 40 years TBT was used as a biocide in anti-fouling paint, commonly known as bo ...
(TBT) and
triphenyltin (TPT) are
endocrine disruptors
Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause ca ...
that have been shown to increase triglyceride storage in
adipocytes
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
. Although they have been widely used in the marine industry since the 1960s, other common sources of human exposure include contaminated seafood and shellfish, fungicides on crops and as antifungal agents used in wood treatments, industrial water systems and textiles. Organotins are also being used in the manufacture of PVC plastics and have been identified in drinking water and food supplies.
Perfluorooctanoic acid
Perfluorooctanoic acid (PFOA; conjugate base perfluorooctanoate; also known colloquially as C8, for its 8 carbon chain structure) is a perfluorinated carboxylic acid produced and used worldwide as an industrial surfactant in chemical processes a ...
(PFOA) is a surfactant used for reduction of friction, and it is also used in nonstick cookware. PFOA has been detected in the blood of more than 98% of the general US population.
It is a potential endocrine disruptor.
Animal studies have shown that prenatal exposure to PFOA is linked to obesity when reaching adulthood.
Future research
Most of the environmental obesogens currently identified are either classified into the category of chemical mimics of metabolic hormones throughout the body or of neurotransmitters within the brain. Because they fall into these two categories, extensive opportunities for complex interactions and varied sites of action as well as multiple molecular targets are open for consideration. Changing dose ranges tend to result in varying phenotypes and timing of exposure, gender, and gender predisposition introduce even more levels of complexity in how these substances effect the human body.
Because the mechanisms behind the different effects of obesogens are so complex and not well understood, the extent to which they play in the current obesity epidemic may be greater than once thought.
Epigenetic changes due to obesogen exposure must also be considered as a possibility, as they open up the potential for misregulated metabolic functions to be passed on from generation to generation. Epigenetic processes via
hypermethylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of regulatory regions could lead to overexpression of different proteins, and therefore, amplification of acquired environmental effects. Research will be required in order to gain a better understanding of the mechanism of action these chemicals are involved in before the extent of the risk of exposure can be determined and methods of prevention and removal from the environment can be established.
See also
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Bariatrics
Bariatrics is the branch of medicine that deals with the causes, prevention, and treatment of obesity.
Terminology
The term ''bariatrics'' was coined around 1965,Dictionary.com, based on Random House Unabridged Dictionary, Random House (2006 ...
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Obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
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Childhood obesity
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Orexigenic
An orexigenic, or appetite stimulant, is a drug, hormone, or compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropeptide Y, which inc ...
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Epidemiology of obesity
Obesity has been observed throughout human history. Many early depictions of the human form in art and sculpture appear obese. However, it was not until the 20th century that obesity became common — so much so that, in 1997, the World Heal ...
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Epidemiology of childhood obesity
References
Further reading
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{{Health issues of plastics
Obesity
Nutrition
Body shape
Receptors