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Epigenetic Transgenerational Effects of Prental Obesogen Exposure

Posted on February 21, 2013

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.

Literature Cited

1. Blumberg B. Obesogens, stem cells and the maternal programming of obesity. Journal of Developmental Origins of Health and Disease. 2011;2(1):3-8.

2. Carnevalli LS, Masuda K, Frigerio F, Le Bacquer O, Um SH, Gandin V, Topisirovic I, Sonenberg N, Thomas G, Kozma SC. S6K1 plays a critical role in early adipocyte differentiation. Dev Cell. 2010;18(5):763-74. PMCID: 2918254. PMID:20493810.

3. Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012;31(1):219-30. PMID:22094013.

4. Chamorro-Garcia R, Sahu M, Abbey RJ, Laude J, Pham N, Blumberg B. Transgenerational Inheritance of Increased Fat Depot Size, Stem Cell Reprogramming, and Hepatic Steatosis Elicited by Prenatal Exposure to the Obesogen Tributyltin in Mice. Environmental health perspectives. 2013. PMID:23322813.

5. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301-13. PMID:18786417.

6. Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 2011;12(11):722-34. PMID:21952300.

7. Cristancho AG, Schupp M, Lefterova MI, Cao S, Cohen DM, Chen CS, Steger DJ, Lazar MA. Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells. Proc Natl Acad Sci U S A. 2011;108(39):16271-6. PMCID: 3182685. PMID:21914845.

8. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-41. PMID:20071471.

9. Garruti G, Cotecchia S, Giampetruzzi F, Giorgino F, Giorgino R. Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome. J Gastrointestin Liver Dis. 2008;17(2):193-8. PMID:18568142.

10. Golub M, Doherty J. Triphenyltin as a potential human endocrine disruptor. J Toxicol Environ Health B Crit Rev. 2004;7(4):281-95. PMID:15205045.

11. Grun F, Blumberg B. Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology. 2006;147(6 Suppl):S50-5. PMID:16690801.

12. Grun F, Watanabe H, Zamanian Z, Maeda L, Arima K, Cubacha R, Gardiner DM, Kanno J, Iguchi T, Blumberg B. Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol. 2006;20(9):2141-55. PMID:16613991.

13. Hatch EE, Nelson JW, Qureshi MM, Weinberg J, Moore LL, Singer M, Webster TF. Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999-2002. Environ Health. 2008;7:27. PMCID: 2440739. PMID:18522739.

14. Heindel JJ. The obesogen hypothesis of obesity: Overview and human evidence. In: Lustig RH, editor. Obesity Before Birth: Maternal and Prenatal Influences on the Offspring. New York: Springer Verlag; 2011. p. 355-66.

15. Herbert A. The fat tail of obesity as told by the genome. Curr Opin Clin Nutr Metab Care. 2008;11(4):366-70. PMID:18541993.

16. Hill JO, Peters JC. Environmental contributions to the obesity epidemic. Science. 1998;280(5368):1371-4. PMID:9603719.

17. Hines EP, White SS, Stanko JP, Gibbs-Flournoy EA, Lau C, Fenton SE. Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life. Mol Cell Endocrinol. 2009;304(1-2):97-105. PMID:19433254.

18. Hoogduijn MJ, Rakonczay Z, Genever PG. The effects of anticholinergic insecticides on human mesenchymal stem cells. Toxicol Sci. 2006;94(2):342-50. PMID:16960032.

19. Janesick A, Blumberg B. Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity. Birth Defects Res C Embryo Today. 2011;93(1):34-50. PMID:21425440.

20. Janesick A, Blumberg B. The Role of Environmental Obesogens in the Obesity Epidemic. In: Lustig RH, editor. Obesity Before Birth: Springer US; 2011. p. 383-99.

21. Kanayama T, Kobayashi N, Mamiya S, Nakanishi T, Nishikawa J. Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway. Mol Pharmacol. 2005;67(3):766-74. PMID:15611480.

22. Kang Q, Song WX, Luo Q, Tang N, Luo J, Luo X, Chen J, Bi Y, He BC, Park JK, Jiang W, Tang Y, Huang J, Su Y, Zhu GH, He Y, Yin H, Hu Z, Wang Y, Chen L, Zuo GW, Pan X, Shen J, Vokes T, Reid RR, Haydon RC, Luu HH, He TC. A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells Dev. 2009;18(4):545-59. PMID:18616389.

23. Kang S, Bennett CN, Gerin I, Rapp LA, Hankenson KD, Macdougald OA. Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem. 2007;282(19):14515-24. PMID:17351296.

24. Kawai M, Mushiake S, Bessho K, Murakami M, Namba N, Kokubu C, Michigami T, Ozono K. Wnt/Lrp/beta-catenin signaling suppresses adipogenesis by inhibiting mutual activation of PPARgamma and C/EBPalpha. Biochem Biophys Res Commun. 2007;363(2):276-82. PMID:17888405.

25. Kirchner S, Kieu T, Chow C, Casey S, Blumberg B. Prenatal exposure to the environmental obesogen tributyltin predisposes multipotent stem cells to become adipocytes. Mol Endocrinol. 2010;24(3):526-39. PMID:20160124.

26. Klimentidis YC, Beasley TM, Lin HY, Murati G, Glass GE, Guyton M, Newton W, Jorgensen M, Heymsfield SB, Kemnitz J, Fairbanks L, Allison DB. Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics. Proc Biol Sci. 2011;278(1712):1626-32. PMCID: 3081766. PMID:21106594.

27. Koebnick C, Smith N, Coleman KJ, Getahun D, Reynolds K, Quinn VP, Porter AH, Der-Sarkissian JK, Jacobsen SJ. Prevalence of extreme obesity in a multiethnic cohort of children and adolescents. J Pediatr. 2010;157(1):26-31 e2. PMID:20303506.

28. La Merrill M, Birnbaum LS. Childhood obesity and environmental chemicals. Mt Sinai J Med. 2011;78(1):22-48. PMCID: 3076189. PMID:21259261.

29. Li X, Pham HT, Janesick AS, Blumberg B. Triflumizole is an obesogen in mice that acts through peroxisome proliferator activated receptor gamma (PPARg). Environmental health perspectives. 2012;in press

30. Li X, Ycaza J, Blumberg B. The environmental obesogen tributyltin chloride acts via peroxisome proliferator activated receptor gamma to induce adipogenesis in murine 3T3-L1 preadipocytes. J Steroid Biochem Mol Biol. 2011;127(1-2):9-15. PMCID: 3281769. PMID:21397693.

31. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations. PLoS One. 2013;8(1):e55387. PMCID: 3554682. PMID:23359474.

32. McCormick DP, Sarpong K, Jordan L, Ray LA, Jain S. Infant Obesity: Are We Ready to Make this Diagnosis? The Journal of Pediatrics. 2010;157(1):15-9.

33. Newbold RR. Perinatal exposure to endocrine disrupting chemicals with estrogenic activity and the development of obesity. In: Lustig RH, editor. Obesity Before Birth: Maternal and Prenatal Influences on the Offspring. New York: Springer Verlag; 2011. p. 367-82.

34. Newbold RR, Padilla-Banks E, Jefferson WN. Environmental estrogens and obesity. Mol Cell Endocrinol. 2009;304(1-2):84-9. PMCID: 2682588. PMID:19433252.

35. Power C, Jefferis BJ. Fetal environment and subsequent obesity: a study of maternal smoking. Int J Epidemiol. 2002;31(2):413-9. PMID:11980805.

36. Rippe JM, Hess S. The role of physical activity in the prevention and management of obesity. J Am Diet Assoc. 1998;98(10 Suppl 2):S31-8. PMID:9787734.

37. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006;7(12):885-96. PMID:17139329.

38. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA. Inhibition of adipogenesis by Wnt signaling. Science. 2000;289(5481):950-3. PMID:10937998.

39. Rubin BS. Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011. PMID:21605673.

40. Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environmental health perspectives. 2001;109(7):675-80. PMID:11485865.

41. Shockley KR, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARgamma2 Regulates a Molecular Signature of Marrow Mesenchymal Stem Cells. PPAR Res. 2007;2007:81219. PMCID: 2234088. PMID:18288266.

42. Stahlhut RW, van Wijgaarden E, Dye TD, Cook S, Swan SH. Concentrations of urinary phthalate metabolites are associated with increased waist circumferece and insulin resistance in adult U.S. males. Environmental health perspectives. 2007;115(6):876-82.

43. Takada I, Kouzmenko AP, Kato S. Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol. 2009;5(8):442-7. PMID:19581903.

44. Takada I, Mihara M, Suzawa M, Ohtake F, Kobayashi S, Igarashi M, Youn MY, Takeyama K, Nakamura T, Mezaki Y, Takezawa S, Yogiashi Y, Kitagawa H, Yamada G, Takada S, Minami Y, Shibuya H, Matsumoto K, Kato S. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol. 2007;9(11):1273-85. PMID:17952062.

45. Tang-Peronard JL, Andersen HR, Jensen TK, Heitmann BL. Endocrine-disrupting chemicals and obesity development in humans: a review. Obes Rev. 2011;12(8):622-36. PMID:21457182.

46. Taveras EM, Rifas-Shiman SL, Belfort MB, Kleinman KP, Oken E, Gillman MW. Weight status in the first 6 months of life and obesity at 3 years of age. Pediatrics. 2009;123(4):1177-83. PMCID: 2761645. PMID:19336378.

47. Tracey R, Manikkam M, Guerrero-Bosagna C, Skinner MK. Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Reproductive Toxicology. 2013;in press.(0).

48. Zamani N, Brown CW. Emerging roles for the transforming growth factor-{beta} superfamily in regulating adiposity and energy expenditure. Endocr Rev. 2011;32(3):387-403. PMID:21173384.


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