Persistent environmental pollutants responsible for obesity epidemic. Prof. Joe Cummins
Metabolic diseases and obesity are on the increase over the last decades. In France, the proportion of population overweight or obese rose 12 % between 1997 and 2003, from 36.7 to 41.6% [1]. In the United States, the prevalence of obesity was 32.2% among adult men and 35.5% among adult women in 2007-2008 [2]; and obesity in adolescence was significantly associated with increased risk of severe obesity in adulthood [3]. In 2011, a national cohort study of infants and toddlers in the US found that nearly one-third were overweight or obese at 9 months and 2 years of age [4].
Obesity is associated with cardiovascular disease and diabetes; while epidemiological data demonstrate a link between obesity and multiple types of cancer. Obesity disrupts the dynamic role of the adipocyte (fat cell) in energy homeostasis, resulting in inflammation and alteration of metabolic signalling. In addition, obesity causes secondary changes related to insulin signalling and lipid deregulation that foster cancer development [5]. The growing epidemic of obesity has alarming health consequences; hence the treatment of obesity deserves serious consideration. In the past, genetic, sociological, and psychological factors have been discussed; but within the last decade, it has become obvious that chemical pollution may be an unexpected and important factor in the obesity epidemic.
The obesogen hypothesis has been put forward for about a decade; it postulates that certain chemical pollutants can promote obesity by altering homeostatic metabolic set-points, disrupting appetite controls, perturbing lipid homeostasis to promote adipocyte (fat cell) hypertrophy (cell enlargement), or stimulating adipogenic pathways that enhance adipocyte hyperplasia (increase in cell number) during development or in adults [6].
Obesogens are environmental chemicals that cause people to become fat analogously to carcinogens for cancer, mutagens for genetic mutations, and teratogens for birth defects. Obesogens are functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, alter metabolic set points, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity. Obesogens appear to be active in all vertebrates.
The chemical pollutants implicated in the fat epidemic are widely recognized, for the most part, as being endocrine disrupters. The main obesogens include tributyltin (TBT), triphenyltin (TPT), bisphenol A (BPA), perfluoroalkyl compounds (PFCs) and polybrominated diphenyl ethers (PBDEs) [7, 8]. TBT and TPT are used for wood preservation, as antifouling pesticide in marine paints, antifungal in textiles and industrial water systems such as cooling tower and refrigeration water systems, wood pulp and paper mill systems, and breweries. Bisphenol A is used primarily to make plastics, and products using bisphenol A-based plastics have been in commerce use since 1957. PFCs are a group of chemical surfactants most notably used in non-stick and stain-resistance applications. They are major persistent organic pollutants. PBDEs are used as flame retardants; like other brominated flame retardants, PBDEs have been used in a wide array of products, including building materials, electronics, furnishings, motor vehicles, airplanes, plastics, polyurethane foams, and textiles.
Along with the persistent organic pollutants (POPs) listed above are a number of well-known POPs including Dichlorodiphenyldichloroethylene (DDE), formed by the loss of hydrogen chloride (dehydrohalogenation) from DDT, Polychlorinated biphenyl (PCB), a very persistent pollutant derived from electrical equipment but now phased out, and combustion products polychlorinated dibenzodioxins and polychlorinated dibenzofurans which have also been implicated in weight gain. In addition, the old pesticides hexachlorobenzene, hexachlorocyclohexane, and oxychlordane all caused weight gain. The plastics additive phthalates used in a large variety of products, from enteric coatings of pharmaceutical pills and nutritional supplements to viscosity control agents, gelling agents, film formers, stabilizers, dispersants, lubricants, binders, emulsifying agents, and suspending agents, have also been tested and found to increase body size and the size of progeny of the exposed parent [9]. Apart from POPs, certain pharmaceutical drugs are also implicated as obesogens. The known environmental and pharmaceutical obesogens and their regulatory status are presented in Tables 1 and 2; it is very likely that the lists will grow [7, 9].
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Tributyltin (TBT) |
Wood preservative, marine paint, textiles, anti-fouling in water systems including breweries used worldwide |
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Triphenyltin (TPT) |
Same as TBT |
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Bisphenol A (BPA) |
A component of plastics used worldwide |
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Perfluoroalkyl compounds(PFCs) |
Chemical surfactants most notably used in non-stick and stain-resistance applications used world wide |
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Polybrominated diphenyl ethers (PBDEs) |
Flame retardants used worldwide in many products, including building materials, electronics, furnishings, motor vehicles, airplanes, plastics, polyurethane foams, and textiles |
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Dichlorodiphenyldichloroethylene (DDE) |
Formed by the loss of hydrogen chloride (dehydrohalogenation) from DDT, which has been banned but persists in the environment |
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Polychlorinated biphenyl (PCB) |
A very persistent pollutant derived from electrical equipment. PCB production was banned by the United States Congress in 1979 and by the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2001; but still found in fish and game |
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Polychlorinated dibenzodioxins (PCDD) |
Dioxins occur as by-products in the manufacture of some organochlorines, in the incineration of chlorine-containing substances such as PVC (polyvinyl chloride), in the chlorine bleaching of paper, and from natural sources such as volcanoes and forest fires |
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Polychlorinated dibenzofurans (PCDF) |
PCDFs tend to co-occur PCDDs; PCDFs can be formed by pyrolysis or incineration at temperatures below 1200 °C of chlorine containing products, such as PVC, PCBs, and other organochlorides, or of non-chlorine containing products in the presence of chlorine donors |
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Hexachlorobenzene |
A fungicide formerly used as a seed treatment, especially on wheat to control the fungal disease bunt. It has been banned globally under the Stockholm Convention on persistent organic pollutants but persists as a POP |
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Hexachlorocyclohexane (lindane) |
Used both as an agricultural insecticide and as a pharmaceutical treatment for lice and scabies; banned in 2009 under the Stockholm Convention on POPs, with exemption for use as a second-line pharmaceutical treatment for lice and scabies |
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Oxychlordane |
The parent compound of oxychlordane is chlordane, banned by US EPA banned in 1988; but chlordane and oxychlordane persist as POPs |
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Phthalates |
Mainly used as plasticizers (substances added to plastics to increase their flexibility, transparency, durability, and longevity), primarily to soften polyvinyl chloride (PVC); they are being phased out of many products in the United States, Canada, and European Union over health concerns. |
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Dithiocarbamates |
Used extensively as seed treatments to control fungi |
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Alkylphenols |
Alkylphenols are xenoestrogens, or man-made estrogen; the European Union has implemented sales and use restrictions on certain applications in which nonylphenols are used because of their alleged 'toxicity, persistence, and the liability to bioaccumulate' but the United States EPA has taken a slower approach to make sure that action is based on “sound science” |
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Diethylstilbestrol (DES) |
A synthetic estrogen that was once prescribed to women to decrease the risk of miscarriage until it was found to be causing abnormalities and cancer in exposed offspring; during the 1960s, DES was used as a growth hormone in the beef and poultry industries, until it was found to cause cancer and phased out in the late 1970 |
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Selective serotonin reuptake inhibitor (SSRI) |
The main use for SSRIs is clinical depression; frequently prescribed for anxiety disorders such as social anxiety, panic disorders, obsessive–compulsive disorder (OCD), eating disorders, chronic pain and occasionally, for posttraumatic stress disorder (PTSD); FDA findings resulted in a black box warning on SSRI and other regarding the increased risk of suicidal behavior in patients younger than 24 |
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Tricyclic antidepressants (TCA) |
For many years TCAs were the first choice for pharmacological treatment of clinical depression; although still considered highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile |
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Atypical antipsychotics |
Typically used extensively to treat schizophrenia or bipolar disorder; also frequently used for agitation associated with dementia, anxiety disorder, and obsessive-compulsive disorder |
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Thiazolidinediones (TZD) |
A class of medications used in the treatment of diabetes type 2 introduced in the late 1990s; TZDs act by activating PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARγ (gamma).When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes |
Endocrine disrupting chemicals (EDCs) affect obesity-related pathways by altering cell signalling involved in weight and lipid homeostasis. Proposed mechanisms include effects on thyroid and steroid hormones, and activation of peroxisome proliferator-activated receptors, which play a major role in adipocyte differentiation and energy storage. Most evidence supporting the hypothesis that EDCs affect obesity comes from laboratory studies and from epidemiological observations [10]. Both obesogenic drugs and chemicals have been shown to target transcription regulators found in gene networks that function to control intracellular lipid homeostasis and proliferation and differentiation of adipocytes. The major group of regulators targeted is one of nuclear hormone receptors known as peroxisome proliferator activated receptors (PPSRs). These hormone receptors sense a variety of metabolic ligands including lipophilic hormones, dietary fatty acids, and their metabolites, and, depending on the levels of these ligands, control transcription of genes involved in lipid balance in the body. In order to become active and function as both metabolic sensors and transcription regulators, the PPAR joins to another receptor known as the 9-cis retinoic acid receptor (RXR). The RXR receptor itself is the second major target of obesogens next to the PPARs [11]. Obesogens basically alter cell signalling pathways leading to overeating.
Prenatal obesogen exposure alters the fate of a type of stem cells in the body to favour the development of fat cells at the expense of other cell types (such as bone). In turn, this makes it likely to increase body weight. Obesogen exposure in utero and/or during the first stages of postnatal growth therefore predispose a child to obesity by influencing all aspects of adipose tissue growth, starting from multipotent stem cells and ending with mature adipocytes [12]. A growing body of evidence suggests that the intrauterine environment has a significant and lasting effect on the long-term health of the growing foetus and the development of metabolic disease in later life, as put forth in the f0etal origins of disease hypothesis (see also [13] Epigenetic Toxicology. SiS41). Metabolic diseases have been associated with alterations in the epigenome that occur without changes in the DNA sequence, such as cytosine methylation of DNA, histone posttranslational modifications, and micro-RNA [14] (Epigenetic Inheritance - What Genes Remember, SiS 41). Epigenetic modifications can be reversed by the addition of methyl donors, such as folic acid in the diet. Epigenetic modifications were not observed in Wistar rats that received a diet containing folic acid. Thus the embryo may not be condemned to obesity provided that the mother has taken folic acid [15].
The discovery of environmental obesogens is a major breakthrough and one that holds great promise in finding remedies as well as prevention for the global epidemic of obesity. Not only are adults subject to the injury of obesogens but unborn and newly born infants may be imprinted for life through the mother’s exposure to obesogens. The offending obesogens still in use must now be banned or phased out as quickly as possible.
Article first published 29/02/12
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Rory Short Comment left 1st March 2012 02:02:45
Yes, it is a major breakthrough but to me it is also a warning sign saying that a lot of our undisciplined use of new chemicals is completely irresponsible driven by greed for money.
Vaikunthanath Kaviraj Comment left 2nd March 2012 06:06:34
I have a feeling that we here have the facile passing of blame to environmental factors - which can at best be triggers and maintainers only - are blamed for something thst was created almost immediately after birth - alterations in the liver enzyme balance, which regulate digestion. These alterations come about from vaccine ingredients. Interacting with the genetic material, the damaged gene will now express the damage instead of its close to perfect natural development, which needs no "improvement by dangerous and experimental vaccines. Bypassing the Neuremberg Code which forbids experiments without INFORMED consent. Since the procedure is entirely experimental, informed consent cannot be given - in formation is still not avaialable.
The mercury in the baccines moreover damages the brain and nervous system. The vagus nerve is normally myelinated between 6-8 months, when teeth appear and the saliva anc stomach acids change and solid food is taken. When then results appear the obvious connections are denied and obesity is but one one result.
I have seen countless articles trying to tie the bowel and obesity problems of children to environmental factors, but they werre the same or worse in the 1800s, when such diseases were not seen from lack of vaccines available and the small percentage of the population subjected to them. With the vaccine craze now nearing its peak with sextavalent vaccines injected with weekly routines nears the height of all medical folly. I think it is time to rethink this strategy as self-defeating in more than one way.
We cannot forget how people like Andy Wakefield have been smeared by Brian Deer and the BMJ. We cannot overlook the scandalous role of the GMC, in cahoots with the previous perverted party of slanderers and give the vax industry a platform where they can shift the blame away from their own brand of poisons.
I am sorry to disagree with the general tenet, and the misinterpretation of the data as causes, while they are but triggers and maintainers. I find the facile blame-laying misleading and tendentious.
Desiree L. Rover Comment left 1st March 2012 20:08:55
Vaccines, at present given within the first 48 hours after birth, are the first and most fundamental disruptors of the metabolic and immune systems. Due to the mantra “Vaccines are safe and effective” vaccination is never mentioned in this devastating role.
This vaccine-induced derangement makes the body very susceptible to the delirerious effects of the many dangerous chemicalls added to the food. It is on top af all this that the new-to-nature substances described in this excellent article seriously aggravate the disbalanced condition. A well orchestrated effort to cull mankind?
joe cummins Comment left 5th March 2012 09:09:24
A reader commented 'As you know both hypo- and hyper-methylation of specific genes can change fetal (metabolic) programming. Godfrey et al. recently proved that greater methylation of RXRA chr9:136355885+ measured at birth was strongly correlated with greater adiposity in later childhood.That’s why it would be better not to say that:Epigenetic modifications can be reversed by the addition of methyl donors, such as folic acid in the diet.. the embryo may not be condemned to obesity provided that the mother has taken folic acid' The nuclear hormone receptor Retinoic X Receptor a (RXRa) is a regulators of cholesterol synthesis and thus cholesterol metabolism.It may help to describe the embryo program for epigenetic deevelopment. Briefly put the program for development of the embryo involves epigentic changes to genes. Epigentic modifications do not alter the DNA code but they modify the expression of genes involved in development. There are several ways that such epigenetic programs may unfold and a major control is the addition of methyl groups to DNA Cytosine [C] in clusters of two letter words CpG (G stands for guanine ) in promoters of major embryo development genes. Such methyl group additions silence the promoters of the genes and the genes can be reactivated by demethylation of CpGs. Methylation patterns are largely established during embryogenesis or in early postnatal life. Following fertilization, maternal and paternal genomes undergo extensive demethylation. This is followed by methylation just prior to implantation of the embryo. DNA methylation also plays a key role in cell differentiation by silencing the expression of specific genes during the development and differentiation of individual tissues. For example, the expression of Oct-4, a key regulator of cellular pluripotency in the early embryo, is permanently silenced by hypermethylation of its promoter , while HoxA5 and HoxB5 which are required for later stages of development are not methylated and silenced until early postnatal life. Environmental pollutants such as arsenic exposure during development are associated with global DNA hypomethylation of GC-rich regions leading to discordant developmental programs. Obesogens have been found to hypomethylate some important regulatory genes while hypermethylating others.
In my report on environmental obesogens I Pointed out rat experiment showing that folate treatment of mothers reduced obesity in offsprings. I appreciate the comment that folate may increase methylation of hypomethlated gene influencing obesity in the embryo, however, the failure of pregnant women to consume folate supplement greatly increases her risk of bearing a child with neurotube defects including Spina bifida and Anencephaly. It is unwise to expose the pregnant woman to folate antimetabolites (such as methotrexate) to reduce methylation of development genes because that drug is known to terminate pregnancy. Women of child bearing age should take folate to reduce the risk of birth defects and that supplement may or may not alleviate obesity in the human child even though it does for rats.
Todd Millions Comment left 8th March 2012 09:09:30
Quite frightening.This list is already too long and the synergies between these items make causal analaysis-problematic.Add gm(bt)crops and sugars too the mix and its even more of a nightmare.
As a stopgap,I have observed that physical 'reminders'(not skinnerian conditioning),can be useful too remind people not too over eat,and this may be of some small use.Specifically-a belt buckle with the top and bottom edges sharpened enough(western style are very good for this),too cause discomfort as the stomach is filled.The constant reminder rather than pain being the oprative mech.I had a similar structure'built in' since birth and I still have the profile of a wet weasel-This isn't genetic I do assure.