The Commonly Overlooked Factor. Commentary on: “Environmental Obesogens and their Impact on Susceptibility to Obesity”

Obesity represents the storage of excess calories as a consequence of an imbalance between calories taken in and calories expended. This statement, although ultimately true, reduces to bare bones the full scenario, which is not as simple as calories in and calories out. Our cells transduce food intake into chemical signals that activate a myriad of biochemical pathways and the synthesis and release of hormonal cues to adjust energy balance. Environmental factors including stress, drugs, microbiome, and pollutants interfere with these signaling pathways, misleading our internal sensors and, consequently, causing energy imbalance (1).

Endocrine disrupting chemicals (EDCs) are a special type of pollutants defined as exogenous chemicals that interfere with any aspect of hormone action (2). A group of EDCs named metabolism disrupting chemicals (MDCs) act on metabolic tissues, principally endocrine pancreas, adipocytes, liver, and brain to promote obesity, insulin resistance, diabetes mellitus, and nonalcoholic fatty liver disease in animal models (3). The number of epidemiological studies about the effects of MDCs increases day-to-day, with most establishing a positive correlation with these disorders (4). Certainly, most of these studies are cross-sectional and do not infer causality, yet longitudinal studies are beginning to emerge and should clarify the relevance of MDCs in causing human metabolic disorders. In any case, the weight of evidence collected over the last 15 years in cellular, animal, and epidemiological studies, indicates that the importance of MDCs in the etiology of metabolic disorders should not be underestimated when compared with other environmental risk factors. The review by Egusquiza and Blumberg brings to our attention how relevant these MDCs named obesogens can be in the etiology of obesity (5).

The obesogen hypothesis formulated by Blumberg’s lab in 2006 raises an adipocyte-centered perspective and defines obesogens as chemicals which promote adipose tissue accumulation in vivo (6). They employed the EDC tributyltin (TBT) as a model of obesogen. TBT has been used as a biocide in antifouling paints for decades, and has recently been found in plastic containers. Like most EDCs, TBT acts at low concentrations, within the levels of human environmental exposure. It binds, with high affinity, peroxisome proliferator-activated receptor γ (PPARγ), the master regulator of adipogenesis, as well as the retinoid X receptor (RXR), and promotes adipogenesis in vitro and fat accumulation in vivo. Research has mostly focused on the consequences of perinatal exposure, revealing that offspring from rodents exposed during pregnancy and lactation to TBT develop obesity. The current mechanism explaining this phenomenon involves changes in the effectiveness of the mesenchymal stem cells progenitor pool, in switching towards the adipocyte lineage at the expense of bone. Other complementary mechanisms include the damage to adipocyte health and dysbiosis of gut microbiome.

One of the most important and worrisome effects of obesogens in mice is that ancestral exposure results in the transmission of obesity phenotypes across more than 3 generations. Early life exposure to the pesticide DDT, as well as other EDCs at relatively high doses, induced obesity in the F3 generation, which were unexposed to these chemicals (7, 8). Yet, little was known up to date about the mechanism underlying transgenerational effects. Egusquiza and Blumberg discuss new work from Blumberg´s lab that begins to uncover how epigenetic modifications are transmitted across generations. They propose that TBT exposure disrupts chromatin architecture and this altered structure might have the capacity of self-reconstructing in unexposed generations leading to epigenomic alterations. This new model is able to embrace DNA methylation, noncoding RNAs, and histone modifications, the 3 types of epigenomic modifications proposed to serve as mediators for epigenetic memory across generations after ancestral exposure to MDCs.

The obesogenic action of EDCs is, of course, not limited to TBT. The review discusses a list of new potential obesogens such as dibutyltin (DBT), bisphenols-S and -F, acrylamide, surfactants, food additives, and pesticides, which are all able to bind to PPARγ and promote adipogenesis.

It is important to bear in mind that the adipocyte-centered perspective of the obesogen hypothesis is probably a simplification of real-life conditions. Energy balance is a tightly regulated process; if obesogens only targeted adipocytes, their action would likely be counteracted by a compensatory response resulting in decreased food intake or increased energy expenditure. In the real world, we are all exposed to a cocktail of EDCs known to target a variety of metabolic tissues other than adipocytes, including the endocrine pancreas, hypothalamus, liver, and skeletal muscle. This combined exposure to multiple EDCs may efficiently alter energy homeostasis, predisposing individuals to obesity and other altered metabolic phenotypes such as insulin resistance, fatty liver, or even weight loss (1).

Although many questions still remain unanswered, the weight of evidence is, likely, high enough to consider MDCs a risk factor for obesity, diabetes mellitus, and other metabolic disorders. Is it justified to recommend avoiding obesogens in humans? We know some readers will find this recommendation not sufficiently justified in the absence of human data unequivocally linking obesogens exposure and obesity. Other readers, on the contrary, will agree with Egusquiza and Blumberg in the adoption of a personal precautionary principle. Results, although mostly obtained from animal experiments, point to multigenerational and transgenerational MDC-induced effects at low doses. Conclusive evidence in humans may take a good number of years. Can we really wait until we have the unequivocal link in humans while both MDC exposure and metabolic disorders continue to grow?

Abbreviations

Abbreviations
 
• EDC

  endocrine disrupting chemical

 
• MDC

  metabolism disrupting chemical

 
• PPARγ

  peroxisome proliferator-activated receptor γ

 
• TBT

  tributyltin

Additional Information

Disclosure Summary: P.A.M. and A.N. have nothing to declare.

Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.