Obesogens: The epigenetic interaction between nature and nurture on risk of obesity
More than 35% of the U.S. population is considered clinically obese (body mass index of > 30), while 68% of the U.S. is considered overweight (body mass index of > 25) 1. Obesity is known to have adverse health effects, impacting the risk and prognosis for a number of diseases, such as coronary heart disease, high blood pressure, liver disease, and Alzheimer’s. A few decades ago, obesity was rarely considered by pediatricians, and typically only in the context of rare genetic disorders, such as Prader-Willi syndrome. With the incidence now on the rise, obese children are at an increased risk for many obesity-related health conditions once restricted to adults 2. Indeed, these rates have rendered type 2 diabetes, once an “adult-onset” disease, a disease now commonly seen in adolescents.
The debate between nature and nurture has persisted through history. Both have long been considered for their influence on incidence rates of diseases like obesity. While technologies have improved our ability to examine the underlying genetic causes, both have failed to sufficiently account for the observed incidence of obesity. Such rapid changes in incidence produces an apparent disparity between genetic and environmental factors. Although the most widely accepted cause of obesity is overconsumption of calorically dense food coupled with diminished physical activity, emerging evidence indicates that environmental factors can predispose individuals to gain weight, irrespective of diet and exercise. In line with this, there is a high rate of obesity in very young children, including infants 3. Whereas one can argue that adolescents, and adults may be consuming more and exercising less than in the past, it is implausible that this would apply to infants. A more probable explanation is that obesity results from prolonged disturbances in the homeostatic regulation of energy metabolism that favors triglyceride storage and adipocyte hypertrophy. This could occur through the prenatal environment causing these infants to be born with an increased level of fat and predisposing them to accumulate fat more readily, or through significant changes in the postnatal environment. In support of the later, animals living in close proximity to humans (e.g. dogs, cats, and laboratory animals such as mice, rats, and primates) have exhibited pronounced increases in obesity over the past few decades 4.
The large differences in DNA methylation observed between human pre-adipocytes and mature adipocytes suggests that epigenetics plays an important role in the process of adipocyte formation. Furthermore, methylation changes in the DNA of blood leukocytes have been observed in obese adolescents 5. Given these key findings on epigenetics and environment on incidence of obesity, the environmental obesogen model was proposed to explain their interaction. This model suggests that chemical exposure during critical stages of development can impact consequent adipopgenesis, lipid balance, hormone synthesis, metabolism, and ultimately obesity. As developmental exposure represents a limited window of increased sensitivity where long-term effects can be established, changes in DNA methylation through obesogens may be a key mechanism to explain the increased rise in obesity, both at the individual and transgenerational level 6. Importantly, obesogens have been shown to deregulate the central hypothalamic–pituitary–adrenal axis and therefore derail many homeostatic mechanisms important for weight control 7. Given their role, coupled with the fact that adipose depots function as endocrine organs that are involved in the feedback system of the body to modify the regulation of appetite and the metabolic integration between organs and inflammatory responses, obesogens have been labeled as endocrine disruptors 8,9. Examples of endocrine-disrupting chemicals include heavy metals, pesticides, solvents, phthalates, and organotins. These chemicals have varied sites of action with complex biological interactions and include substances that have similar effects to the hormones they mimic as well substances that act as inhibitors of endogenous hormone action. Beyond alteration of hormonal control of appetite and satiety, obesogens can act indirectly to promote obesity by changing basal metabolic rate, shifting energy balance to favor storage of calories, and by promoting food storage via gut micriobiota interactions 10,11.
The specific mechanisms through which environmental obesogens contribute to the generation of obesity remain largely unknown. However, obesogens have been shown to perturb various endocrine axes, generally targeting nuclear receptors, including sex steroid receptors, the gamma peroxisome proliferator receptors (PPARγ), the retinoic acid receptors (RXR), and the glucocorticoid receptor. Importantly, all of these targets have a role in adipocyte physiology and the regulation of energy homeostasis 12. Specifically, many obesogens have been shown to act through the peroxisome proliferator activated receptors (PPARs), the master regulators of adipogenesis. Two prime obesogen candidates are tributyltin (TBT) and tetrabromobisphenol A (TBBPA), toxic and widespread pollutants that have been shown to interfere with hypothalamic gene regulations through RXR/PPARγ activation 13. These chemicals are able to modulate critical steps of adipogenesis in vitro and in vivo, predisposing mesenchymal stem cells to become adipocytes by epigenetic imprinting. For instance, the effects of TBT exposure on fat depot size and stem cell reprogramming have been shown to persist through the F3 generation following exposure of pregnant F0 mice 14. F3 mice are never exposed to the obesogen directly, and therefore the effects must result from genetic and epigenetic alterations. Additionally, following exposure to a mixture of plastics in gestating F0 generation female rats during embryonic days 8-14, significant increases in the incidence of diseases in both the F1 and F3 generation animals were detected. Importantly, the F3 animals had an increased prevalence of obesity 15. In line with these findings, exposure of adolescent mice to TBT has shown to increase fat depot size and accumulation of lipids in the liver, leading to insulin resistance 16. Similar transgenerational effects of obesogens have been observed with estrogenic endocrine disruptors such as diethylstilbestrol (DES), bisphenol A (BPA), and DDT 17. Finally, an association between the hyper-methylation status of genes such as RXRα in human umbilical cord tissue and the eventual development of childhood obesity was recently found in two longitudinal studies 18.
Genetic variation likely plays an important role in determining the inter-individual differences in susceptibility or resistance to the current “obesogenic” environment. Twin studies have shown that genetic factors explain over 40% of the variance in BMI and risk of obesity 19. However, as twins share a prenatal environment, the potential interaction with epigenetic changes through maternal nutrition and health, as well as through obesogenic exposure in-utero cannot be ruled out. In line with this, an emerging idea is that certain epigenetic changes may only be detrimental in the presence of concomitant nucleotide base mutations in functionally relevant genes. Conversely, data shows that epigenetic changes increase the rate of spontaneous genomic DNA mutations nearby, and that nucleotide base mutations in genomic DNA are associated with epigenetic changes in the same region 20. Therefore, identifying the molecular mechanisms involved in endocrine disruption through obesogens must be broadened to include the possibility that epigenetic and genetic mechanisms interact in potentially synergistic ways. Techniques that are able to detect both of these kinds of changes, such as pyrosequencing and deep sequencing, will be imperative towards a comprehensive understanding of the etiology of obesity-specific epigenetic risk profiles and the role of obesogens.
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