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Welcome to PSR's Environmental Health Policy Institute, where we ask questions -- then we ask the experts to answer them. Join us as physicians, health professionals, and environmental health experts share their ideas, inspiration, and analysis about toxic chemicals and environmental health policy.

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Epigenetic Transgenerational Effects of Prental Obesogen Exposure

By Amanda Janesick and Bruce Blumberg, PhD

Obesity and related disorders are a public health epidemic, particularly in the U.S. Currently 34% of the U.S. population is clinically obese (BMI > 30) and 68% are overweight (BMI > 25), more than double the worldwide average and 10-fold higher than Japan and South Korea 8. Genetics 15 and behavioral factors such as smoking 35, stress 9, a sedentary lifestyle 36 and excessive consumption of food 16 are the typically cited causes of obesity. However, environmental factors, including exposure to xenobiotic chemicals, are under-studied compared with diet and lifestyle, in understanding the development of obesity. Since the magnitude of the burden on the U.S. healthcare system exceeds $208 billion annually 3, a detailed study of the role of environmental chemicals on the etiology of obesity is timely and important.

New approaches are needed

The rate of obesity in very young children, even infants has been increasing alarmingly 27, 32, 46. While it is possible that the typical infant now consumes far more calories than in the past and doesn't exercise as much as previous generations did, it is more likely that the infant was born with more fat, and/or that something about the pre-and postnatal environment differs significantly from the past. An intriguing recent study showed that animals living in proximity to humans including pets (cats and dogs), laboratory animals (rats, mice, 4 species of primates) and feral rats exhibited significant increases in obesity over the past several decades 26. It is particularly noteworthy that these included laboratory animals living in strictly controlled environments and feral animals living in cities 26. The likelihood of 24 animal populations from 8 different species all showing a positive trend in weight over the past few decades by chance was estimated at about 1 in ten million 26. Although the underlying cause remains unknown, the most reasonable inference is that something in the environment has changed, making these animals obese in parallel with humans.

The obesogen hypothesis

In 2006, we proposed the existence of endocrine disrupting chemicals (EDCs) that could influence adipogenesis and obesity and be important, yet unsuspected players in the obesity epidemic. These “obesogens” are chemicals that promote obesity by increasing the number of fat cells and/or the storage of fat into existing cells. Obesogens can act indirectly by changing basal metabolic rate, by shifting energy balance to favor calorie storage, and by altering hormonal control of appetite and satiety 1, 14, 19-20, 28, 33. Several obesogenic chemicals have been identified in recent years, underscoring the relevance of this new model. Estrogenic EDCs such as diethylstilbestrol (DES) 34 and bisphenol A (BPA) 39-40, organotins such as tributyltin (TBT) 12, perfluorooctanoates 17 and fungicides such as triflumizole 29 are obesogenic in animals. Urinary phthalate levels were correlated with increased waist diameter 13, 42 and high levels of several persistent organic pollutants (e.g., DDE, HCB, polybrominated diphenylethers) were linked with obesity in humans 45.

How do obesogens act?

The only obesogens with a known pathway of action are triflumizole (TFZ), TBT, and triphenyltin (TPT). TPT is used in agriculture and TBT in industry. Human exposure occurs through dietary sources (seafood and shellfish), from organotin use as fungicides and miticides on food crops, in wood treatments, industrial water systems, textiles, and via leaching from organotin-stabilized PVC water pipes, and other plastics 10-11. TBT and TPT are nanomolar affinity ligands for two nuclear receptors critical for adipocyte development: the 9-cis retinoic acid receptor (RXR) and peroxisome proliferator activated receptor gamma (PPARγ) 12, 21. TBT and TFZ promotes adipogenesis in murine 3T3-L1 pre-adipocytes 12, 21 and in human and mouse multipotent mesenchymal stromal cells (MSCs, a.k.a. mesenchymal stem cells) via a PPARγ-dependent pathway 25, 29-30. In utero TBT or TFZ exposure leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and increased adipose depot mass in adults 12, 29.

Adipogenesis in a nutshell

Adipogenesis is a differentiation event in the mesodermal lineage in which MSCs or their more lineage-restricted derivatives give rise to adipocytes 6, 37. MSCs reside largely in the perivascular niche of most organs 5. However, relatively little is known about the mechanisms and intermediates through which MSCs become committed to the adipocyte lineage and how this process might be influenced by EDCs. MSCs give rise to both adipocytes and osteoblasts; the commitment to one or the other lineage is mutually exclusive 41. Expression of PPARγ commits cells to the adipogenic lineage whereas Wnt signaling inhibits PPARγ expression and diverts MSCs toward the osteogenic lineage 7, 43. Repression of non-canonical Wnt-5a 44 and canonical Wnt-3a/10b 23-24, 38 signaling together with active BMP/TGF-β and PI3K/Akt signaling 2, 22, 48 is required for MSCs to proceed toward the adipogenic and away from the osteogenic lineage.

EDCs and reprogramming of MSC fate

The confluence of multiple signaling pathways to allocate MSCs between adipogenic and osteogenic fates offers many possibilities for disruption by EDCs; however, only a few studies have tested how EDCs might influence MSC fate. The pesticides chlorpyrifos and carbofuran inhibited the ability of MSCs to differentiate into bone 18 but the potential of these cells to differentiate into fat was not tested. We found that prenatal treatment with the environmental obesogens, TBT, triflumizole or the pharmaceutical obesogen, rosiglitazone (ROSI), reprogrammed MSCs to favor the adipocyte lineage at the expense of the bone lineage 25, 29. Adipose-derived MSCs were enriched in cells committed to the adipogenic lineage after prenatal treatment and the promoter of a key adipogenic marker (FABP4) was under-methylated in TBT-treated animals, suggesting an epigenetic mechanism 25.

We recently demonstrated that prenatal exposure to low, environmentally relevant doses of TBT via the drinking water led to increased fat depot size, adipocyte size and adipocyte number. Exposure also reprogrammed MSCs to favor the adipocyte lineage and caused hepatic steatosis and altered hepatic gene expression. These effects persisted through at least the F3 generation after exposure of pregnant F0 animals 4. This suggests that prenatal TBT exposure has caused heritable alterations in the germ cell genome of the directly exposed F1 fetuses that predisposes the MSC compartment toward the adipocyte lineage and away from the osteogenic lineage. Skinner and colleagues recently showed that prenatal exposure to BPA, dibutyl

phthalate, diethylhexyl phthalate or JP-8 jet fuel caused a variety of transgenerational phenotypes, including obesity in F3 animals accompanied by sperm epimutations 31, 47. Nothing is currently known about how obesogen exposure causes heritable, transgenerational changes in the genome that alter MSC fate but this is an active area of investigation.

Future directions

There is an urgent need to understand the mechanisms underlying the predisposition to obesity and related disorders. While evidence implicating environmental influences continues to mount, the study of environmental factors in obesity is only beginning, and the mechanisms of the environmentally initiated obesity (i.e., other than by foods or lifestyles) remain largely unknown. The obesogen hypothesis opened a new area of research into obesity by connecting endocrine disruptor research with developmental origins of disease. We do not currently know to what extent obesogen exposure predisposes humans to obesity compared with other known factors such as the timing, amount and nature of calories consumed vs. physical activity. Nothing is known about how obesogen exposure interacts with diet and other lifestyle factors such as stress, amount of sleep, virus exposure, gut microbes, and genetic factors. The obesogen hypothesis fits well with the developmental origins model to provide molecular explanations for how obesity might begin in the womb.  Epigenetics is predicted to influence early programming events in the MSC compartment, where cells receive cues from their local environment that determine the potential for future differentiation.  Since critical events in adipose tissue development occur early in life, exposure to obesogenic chemicals during these time windows can alter epigenetic programming events to predispose a stem or progenitor cell towards a particular lineage. Evidence to support an epigenetic basis for obesogen action is only now emerging 4, 25  as is evidence supporting epigenetic effects of EDC exposure on fertility, behavior, stress and other endpoints 31, 47. The field of adipose development, beginning at the stem cell stage, is still in its infancy, and future research should endeavor to understand whether and how this process can be misregulated by obesogens to produce obesity and related disorders.

Acknowledgements: Work in the authors’ laboratory was supported by grants from the NIH (ES-015849, ES021020) to B.B. A.J. was a pre-doctoral trainee of NSF IGERT DGE 0549479.

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