Obesogens: Definition, mechanisms of action, potential industrial chemicals and pharmaceuticals

Abstract

The incidence of obesity and related diseases increased dramatically in the last decade. Some endocrine disruptors were shown to interact with metabolic processes via various cellular mechanisms, disrupt homeostasis in adipose tissue, resulting in weight gain and obesity. These chemicals are called “obesogens”. Today, with the increased use of industrial chemicals, individuals are exposed to a mixture of chemicals at very low doses. Most of these industrial chemicals have been investigated for their possible endocrine disrupting and obesogenic effects. Beside these chemicals, pharmaceuticals can also have similar adverse effects, however, limited studies have been performed to investigate such effects of drugs. Furthermore, there are few studies investigating the relationship between prenatal exposure to pharmaceuticals and childhood obesity. Therefore, to clarify the endocrine disrupting and obesogenic effects of the pharmaceuticals, which are prescribed during pregnancy, mechanistic studies should be performed, and necessary precautions should be taken. In this paper, we reviewed the mechanisms of obesogens, briefly overview several well-known obesogenic industrial chemicals and focused more on potential obesogenic pharmaceuticals.

Keywords

• Endocrine disruptors
• Obesogens
• Adipogenesis
• Lipogenesis
• Pharmaceuticals

References

1. Ahmed, S., & Atlas, E. (2016). Bisphenol S- and bisphenol A-in- duced adipogenesis of murine preadipocytes occurs through direct peroxisome proliferator-activated receptor gamma acti- vation. International Journal of Obesity (2005), 40(10), 1566–1573. https://doi.org/10.1038/IJO.2016.95
2. Albaugh, V. L., Judson, J. G., She, P., Lang, C. H., Maresca, K. P., Joyal, J. L., & Lynch, C. J. (2011). Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mo- lecular Psychiatry, 16(5), 569–581. https://doi.org/10.1038/MP.2010.33
3. Albert, O., Desdoits-Lethimonier, C., Lesné, L., Legrand, A., Guillé, F., Bensalah, K., … Jégou, B. (2013). Paracetamol, aspirin and in- domethacin display endocrine disrupting properties in the adult human testis in vitro. Human Reproduction (Oxford, England), 28(7), 1890–1898. https://doi.org/10.1093/humrep/det112
4. Alonso-Magdalena, P., Laribi, O., Ropero, A. B., Fuentes, E., Ripoll, C., Soria, B., & Nadal, A. (2005). Low doses of bisphenol A and di- ethylstilbestrol impair Ca2+ signals in pancreatic α-cells through a nonclassical membrane estrogen receptor within intact islets of Langerhans. Environmental Health Perspectives, 113(8), 969–977. https://doi.org/10.1289/ehp.8002
5. Arterburn, D., Sofer, T., Boudreau, D., Bogart, A., Westbrook, E., Theis, M., … Haneuse, S. (2016). Long-Term Weight Change after Initiating Second-Generation Antidepressants. Journal of Clinical Medicine, 5(4), 48-60. https://doi.org/10.3390/jcm5040048
6. Atli, O., Baysal, M., Aydogan-Kilic, G., Kilic, V., Ucarcan, S., Kara- duman, B., & Ilgin, S. (2017). Sertraline-induced reproductive toxicity in male rats: Evaluation of possible underlying mecha- nisms. Asian Journal of Andrology, 19(6), 672–679. https://doi. org/10.4103/1008-682X.192637
7. Autrup, H., Barile, F. A., Berry, S. C., Blaauboer, B. J., Boobis, A., Bolt, H., … Vermeulen, N. P. (2020). Human exposure to synthetic en- docrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable en- docrine activity. How to evaluate the risk of the S-EDCs? Toxicol- ogy in Vitro, 67, 104861. https://doi.org/10.1016/J.TIV.2020.104861
8. Baillie-Hamilton, P. F. (2002). Chemical toxins: A hypothesis to explain the global obesity epidemic. Journal of Alterna- tive and Complementary Medicine, 8(2), 185–192. https://doi. org/10.1089/107555302317371479

9. Bashshur, R. L., Mandil, S. H., & Shannon, G. W. (2002). Global as- sessment of the state-of-the-science of endocrine disruptors - Chapter 1: Executive summary. Telemedicine Journal and E-Health, 8(1), 95–107. https://doi.org/10.1089/15305620252933437
10. Bastos Sales, L., Kamstra, J. H., Cenijn, P. H., van Rijt, L. S., Hamers, T., & Legler, J. (2013). Effects of endocrine disrupting chemicals on in vitro global DNA methylation and adipocyte differentiation. Toxicology in Vitro, 27(6), 1634–1643. https://doi.org/10.1016/J. TIV.2013.04.005
11. Blumenthal, S. R., Castro, V. M., Clements, C. C., Rosenfield, H. R., Murphy, S. N., Fava, M., … Perlis, R. H. (2014). An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry, 71(8), 889–896. https://doi.org/10.1001/ja- mapsychiatry.2014.414
12. Buck Louis, G. M., Chen, Z., Kim, S., Smarr, M. M., & Kannan, K. (2017). Male urinary paracetamol and semen quality. Andrology, 5(6), 1082–1088. https://doi.org/10.1111/andr.12413
13. Casals-Casas, C., & Desvergne, B. (2011). Endocrine Disruptors: From Endocrine to Metabolic Disruption. Annual Review of Physi- ology, 73(1), 135–162. https://doi.org/10.1146/annurev-physi- ol-012110-142200
14. Chamorro-Garcia, R., Diaz-Castillo, C., Shoucri, B. M., Käch, H., Leavitt, R., Shioda, T., & Blumberg, B. (2017). Ancestral perina- tal obesogen exposure results in a transgenerational thrifty phenotype in mice. Nature Communications, 8(1). https://doi. org/10.1038/s41467-017-01944-z
15. Chamorro-García, R., Sahu, M., Abbey, R. J., Laude, J., Pham, N., & Blumberg, B. (2013). 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, 121(3), 359–366. https://doi. org/10.1289/ehp.1205701
16. Chawla, S., Kaushik, N., Singh, N. P., Ghosh, R. K., & Saxena, A. (2013). Effect of addition of either sitagliptin or pioglitazone in patients with uncontrolled type 2 diabetes mellitus on metfor- min: A randomized controlled trial. Journal of Pharmacology and Pharmacotherapeutics, 4(1), 27–32. https://doi.org/10.4103/0976- 500X.107656
17. Chu, D. T., Malinowska, E., Jura, M., & Kozak, L. P. (2017). C57BL/6J mice as a polygenic developmental model of diet-induced obesity. Physi- ological Reports, 5(7), e13093. https://doi.org/10.14814/phy2.13093
18. Cohen, I. C., Cohenour, E. R., Harnett, K. G., & Schuh, S. M. (2021). BPA, BPAF and TMBPF Alter Adipogenesis and Fat Accumulation in Human Mesenchymal Stem Cells, with Implications for Obesi- ty. International Journal of Molecular Sciences, 22(10), 5363. https:// doi.org/10.3390/ijms22105363
19. Darbre, P. D. (2017). Endocrine Disruptors and Obesity. Current Obesity Reports, 6(1), 18–27. https://doi.org/10.1007/s13679-017-0240-4
20. Davis, K. E., Carstens, E. J., Irani, B. G., Gent, L. M., Hahner, L. M., & Clegg, D. J. (2014). Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Hormones and Behavior, Vol. 66, pp. 196–207. Academic Press Inc. https://doi.org/10.1016/j.yhbeh.2014.02.004
21. De Cock, M., & Van de Bor, M. (2014). Obesogenic effects of endocrine disruptors, what do we know from animal and hu- man studies? Environment International, 70, 15–24. https://doi. org/10.1016/j.envint.2014.04.022
22. Feige, J. N., Gelman, L., Rossi, D., Zoete, V., Métivier, R., Tudor, C.,… Desvergne, B. (2007). The endocrine disruptor monoethyl- hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis. The Journal of Biological Chemistry, 282(26), 19152–19166. https://doi. org/10.1074/JBC.M702724200
23. Foley, B., Clewell, R., & Deisenroth, C. (2015). Development of a Human Adipose-Derived Stem Cell Model for Characterization of Chemical Modulation of Adipogenesis. Applied In Vitro Toxicology, 1(1), 66–78. https://doi.org/10.1089/aivt.2014.0007
24. Fürnsinn, C., & Waldhäusl, W. (2002). Thiazolidinediones: Meta- bolic actions in vitro. Diabetologia, Vol. 45, pp. 1211–1223. https:// doi.org/10.1007/s00125-002-0899-1
25. Gafoor, R., Booth, H. P., & Gulliford, M. C. (2018). Antidepressant utilisation and incidence of weight gain during 10 years’ follow- up: Population based cohort study. BMJ (Online), 361. https://doi. org/10.1136/bmj.k1951
26. Greenberg, E. R., Barnes, A. B., Resseguie, L., Barrett, J. A., Burn- side, S., Lanza, L. L., … Colton, T. (1984). Breast Cancer in Moth- ers Given Diethylstilbestrol in Pregnancy. New England Jour- nal of Medicine, 311(22), 1393–1398. https://doi.org/10.1056/ nejm198411293112201
27. Gregorian Jr, R. S., Golden, K. A., Bahce, A., Goodman, C., & Kwong, W. J. (2002). Antidepressant-Induced Sexual Dysfunction. The Annals of pharmacotherapy, 36(10), 1577–1589. https://doi. org/10.1345/aph.1A195.
28. Griffin, M. D., Pereira, S. R., DeBari, M. K., & Abbott, R. D. (2020). Mechanisms of action, chemical characteristics, and model systems of obesogens. BMC Biomedical Engineering, 2(1), 1–13. https://doi.org/10.1186/s42490-020-00040-6
29. Grün, F., & Blumberg, B. (2006a). Environmental obesogens: Or- ganotins and endocrine disruption via nuclear receptor signaling. Endocrinology, Vol. 147. https://doi.org/10.1210/en.2005-1129
30. Grün, F., Watanabe, H., Zamanian, Z., Maeda, L., Arima, K., Cubacha, R., … Blumberg, B. (2006b). Endocrine-disrupting organotin com- pounds are potent inducers of adipogenesis in vertebrates. Mo- lecular Endocrinology, 20(9), 2141–2155. https://doi.org/10.1210/ me.2005-0367
31. Gupta, R., Kumar, P., Fahmi, N., Garg, B., Dutta, S., Sachar, S., … Vimaleswaran, K. S. (2020). Endocrine disruption and obesity: A current review on environmental obesogens. Current Research in Green and Sustainable Chemistry, 3. https://doi.org/10.1016/J. CRGSC.2020.06.002
32. Haliakon, S., Doare, L., Foufelle, F., Kergoat, M., Guerre-Millo, M., Berthault, M.-F., … Ferre, P. (1997). Pioglitazone Induces In Vivo Adipocyte Differentiation in the Obese Zucker fa/fa Rat. Diabetes, 46(9), 1393–1399. https://doi.org/10.2337/diab.46.9.1393
33. Hansen, C. H., Larsen, L. W., Sørensen, A. M., Halling-Sørensen, B., & Styrishave, B. (2017). The six most widely used selective serotonin reuptake inhibitors decrease androgens and increase estrogens in the H295R cell line. Toxicology in Vitro, 41, 1–11. https://doi. org/10.1016/j.tiv.2017.02.001
34. Hao, C., Cheng, X., Guo, J., Xia, H., & Ma, X. (2013). Perinatal exposure to diethyl-hexyl-phthalate induces obesity in mice. Frontiers in Bio- science (Elite Edition), 5(2), 725–733. https://doi.org/10.2741/E653
35. Hao, C. J., Cheng, X. J., Xia, H. F., & Ma, X. (2012a). The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice. Toxicology and Applied Pharmacology, 263(1), 102–110. https://doi.org/10.1016/j.taap.2012.06.003
36. Hao, C. J., Cheng, X. J., Xia, H. F., & Ma, X. (2012b). The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice. Toxicology and Applied Pharmacology, 263(1), 102–110. https://doi.org/10.1016/j.taap.2012.06.003
37. Hatch, E. E., Troisi, R., Palmer, J. R., Wise, L. A., Titus, L., Strohsnitter, W. C., … Hoover, R. N. (2014). Prenatal diethylstilbestrol exposure and risk of obesity in adult women. Journal of Developmental Ori- gins of Health and Disease, 6(3), 201–207. https://doi.org/10.1017/ S2040174415000033
38. Hausman, G. J., Poulos, S. P., Pringle, T. D., & Azain, M. J. (2008). The influence of thiazolidinediones on adipogenesis in vitro and in vivo: potential modifiers of intramuscular adipose tissue deposi- tion in meat animals. Journal of Animal Science, Vol. 86. https://doi. org/10.2527/jas.2007-0219
39. Heitzer, M. D., Wolf, I. M., Sanchez, E. R., Witchel, S. F., & DeFran- co, D. B. (2007). Glucocorticoid receptor physiology. Reviews in Endocrine and Metabolic Disorders, Vol. 8, pp. 321–330. Springer. https://doi.org/10.1007/s11154-007-9059-8
40. Hill, J. O., Wyatt, H. R., & Peters, J. C. (2012). Energy balance and obesity. Circulation, 126(1), 126–132. https://doi.org/10.1161/CIR- CULATIONAHA.111.087213
41. Homma, H., Kurachi, H., Nishio, Y., Takeda, T., Yamamoto, T., Adachi, K., … Murata, Y. (2000). Estrogen suppresses transcription of lipopro- tein lipase gene. Existence of a unique estrogen response element on the lipoprotein lipase promoter. Journal of Biological Chemistry, 275(15), 11404–11411. https://doi.org/10.1074/jbc.275.15.11404
42. Hoover, R. N., Hyer, M., Pfeiffer, R. M., Adam, E., Bond, B., Cheville, A. L., … Troisi, R. (2011). Adverse Health Outcomes in Women Ex- posed In Utero to Diethylstilbestrol. New England Journal of Medi- cine, 365(14), 1304–1314. https://doi.org/10.1056/nejmoa1013961
43. Jacobsen, N. W., Hansen, C. H., Nellemann, C., Styrishave, B., & Hal- ling-Sørensen, B. (2015). Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay. Toxicology in Vitro, 29(7), 1729–1735. https://doi.org/10.1016/j.tiv.2015.07.005
44. Janesick, A., & Blumberg, B. (2012). Obesogens, stem cells and the developmental programming of obesity. International Journal of Andrology, Vol. 35, pp. 437–448. NIH Public Access. https://doi. org/10.1111/j.1365-2605.2012.01247.x
45. Janesick, A. S., Dimastrogiovanni, G., Vanek, L., Boulos, C., Cham- orro-García, R., Tang, W., & Blumberg, B. (2016). On the utility of ToxCastTM and ToxPi as methods for identifying new obesogens. Environmental Health Perspectives, 124(8), 1214–1226. https://doi. org/10.1289/ehp.1510352
46. Janesick, Amanda, & Blumberg, B. (2011). Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity. Birth Defects Research Part C: Embryo Today: Reviews, 93(1), 34–50. https://doi.org/10.1002/BDRC.20197
47. Jensen, E. T., & Longnecker, M. P. (2014). Pharmacologic sex hor- mones in pregnancy in relation to offspring obesity. Obesity, 22(11), 2406–2412. https://doi.org/10.1002/oby.20778
48. Kanayama, T., Kobayashi, N., Mamiya, S., Nakanishi, T., & Nishikawa,
49. J. I. (2005). Organotin compounds promote adipocyte differentia- tion as agonists of the peroxisome proliferator-activated recep- tor γ/retinoid X receptor pathway. Molecular Pharmacology, 67(3), 766–774. https://doi.org/10.1124/mol.104.008409
50. Kersten, S. (2001). Mechanisms of nutritional and hormonal regu- lation of lipogenesis. EMBO Reports, 2(4), 282–286. https://doi. org/10.1093/embo-reports/kve071
51. Kirchner, S., Kieu, T., Chow, C., Casey, S., & Blumberg, B. (2010). Pre- natal exposure to the environmental obesogen tributyltin predis- poses multipotent stem cells to become adipocytes. Molecular En- docrinology, 24(3), 526–539. https://doi.org/10.1210/me.2009-0261
52. Koya, D., & Kanasaki, K. (2011). Biology of obesity: Lessons from animal models of obesity. Journal of Biomedicine and Biotechnol- ogy, Vol. 2011. https://doi.org/10.1155/2011/197636
53. La Merrill, M. A., Vandenberg, L. N., Smith, M. T., Goodson, W., Browne, P., Patisaul, H. B., … Zoeller, R. T. (2020). Consensus on the key characteristics of endocrine-disrupting chemicals as a ba- sis for hazard identification. Nature Reviews Endocrinology, 16(1), 45–57. https://doi.org/10.1038/s41574-019-0273-8
54. La Merrill, M., & Birnbaum, L. S. (2011). Childhood obesity and environmental chemicals. Mount Sinai Journal of Medicine, 78(1), 22–48. https://doi.org/10.1002/msj.20229
55. Lebovitz, H. E. (2019). Thiazolidinediones: the Forgotten Diabetes Medications. Current Diabetes Reports, Vol. 19, pp. 1–13. Springer. https://doi.org/10.1007/s11892-019-1270-y
56. Lefterova, M. I., & Lazar, M. A. (2009). New developments in adipo- genesis. Trends in Endocrinology and Metabolism, 20(3), 107–114. https://doi.org/10.1016/j.tem.2008.11.005
57. Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Will- son, T. M., & Kliewer, S. A. (1995). An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated re- ceptor γ (PPARγ). Journal of Biological Chemistry, 270(22), 12953– 12956. https://doi.org/10.1074/jbc.270.22.12953
58. Li, X., Ycaza, J., & Blumberg, B. (2011). The environmental obeso- gen tributyltin chloride acts via peroxisome proliferator activated receptor gamma to induce adipogenesis in murine 3T3-L1 pre- adipocytes. Journal of Steroid Biochemistry and Molecular Biology, 127(1–2), 9–15. https://doi.org/10.1016/j.jsbmb.2011.03.012
59. Liew, Z., Nohr, E. A., Morgen, C. S., Ernst, A., Li, J., Sørensen, T. I. A., & Olsen, J. (2019). Prenatal Exposure to Acetaminophen and Overweight in Childhood. Obesity, 27(8), 1314–1322. https://doi. org/10.1002/oby.22526
60. Lind, D. V., Main, K. M., Kyhl, H. B., Kristensen, D. M., Toppari, J., An- dersen, H. R., … Jensen, T. K. (2017). Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: A cohort study of 1027 mother-child pairs. Human Reproduc- tion, 32(1), 223–231. https://doi.org/10.1093/humrep/dew285
61. Lord, C. C., Wyler, S. C., Wan, R., Castorena, C. M., Ahmed, N., Mathew, D., … Elmquist, J. K. (2017). Atypical antipsychotic causes weight gain by targeting serotonin receptor 2C. Clinical Pharma- cist, 9(10), 3402–3406. https://doi.org/10.1211/CP.2017.20203665
62. MacKay, H., & Abizaid, A. (2018). A plurality of molecular targets: The receptor ecosystem for bisphenol-A (BPA). Hormones and Behavior, 101(November), 59–67. https://doi.org/10.1016/j.yh- beh.2017.11.001
63. Maloney, E. K., & Waxman, D. J. (1999). trans-Activation of PPA- Ralpha and PPARgamma by structurally diverse environmental chemicals. Toxicology and Applied Pharmacology, 161(2), 209–218. https://doi.org/10.1006/TAAP.1999.8809
64. Manikkam, M., Tracey, R., Guerrero-Bosagna, C., & Skinner, M. K. (2013). Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PloS One, 8(1). https://doi.org/10.1371/JOURNAL.PONE.0055387
65. Masuno, H., Kidani, T., Sekiya, K., Sakayama, K., Shiosaka, T., Yama- moto, H., & Honda, K. (2002). Bisphenol A in combination with insulin can accelerate the conversion of 3T3-L1 fibroblasts to adipocytes. Journal of Lipid Research, 43(5), 676–684. https://doi. org/10.1016/S0022-2275(20)30108-5
66. Mauvais-Jarvis, F. (2011). Estrogen and androgen receptors: Regu- lators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab, 22(1), 24–33. https://doi. org/10.1016/j.tem.2010.10.002
67. McTernan, P. G., Harte, A. L., Anderson, L. A., Green, A., Smith, S. A., Holder, J. C., … Kumar, S. (2002). Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. Diabetes, 51(5), 1493–1498. https://doi.org/10.2337/dia- betes.51.5.1493
68. Miettinen, S., Sarkanen, J. R., & Ashammakhi, N. (2008). Adipose Tissue and Adipocyte Differentiation: Molecular and Cellular As- pects and Tissue Engineering Applications. Topics in Tissue Engi- neering, 4, 1–26.
69. Moazzam, S., Jarmasz, J. S., Jin, Y., Siddiqui, T. J., & Cattini, P. A. (2021). Effects of high fat diet-induced obesity and pregnancy on prepartum and postpartum maternal mouse behavior. Psy- choneuroendocrinology, 126, 105147. https://doi.org/10.1016/j. psyneuen.2021.105147
70. Montagnini, B. G., Bortolan, S., Santos, B. D. Dos, Moreno, A. P., De Azevedo Camin, N., Gerardin, D. C. C., & Moreira, E. G. (2013). Eval- uation of escitalopram, sertraline, and methylphenidate in the immature rat uterotrophic assay. International Journal of Toxicol- ogy, 32(6), 426–430. https://doi.org/10.1177/1091581813509674
71. Moraitis, A. G., Block, T., Nguyen, D., & Belanoff, J. K. (2017, Janu- ary 1). The role of glucocorticoid receptors in metabolic syn- drome and psychiatric illness. Journal of Steroid Biochemistry and Molecular Biology, Vol. 165, pp. 114–120. Elsevier Ltd. https://doi. org/10.1016/j.jsbmb.2016.03.023
72. Mori, Y., Murakawa, Y., Okada, K., Horikoshi, H., Yokoyama, J., Ta- jima, N., & Ikeda, Y. (1999). Effect of troglitazone on body fat distri- bution in type 2 diabetic patients. Diabetes Care, 22(6), 908–912. https://doi.org/10.2337/diacare.22.6.908
73. Moseti, D., Regassa, A., & Kim, W. K. (2016). Molecular regulation of adipogenesis and potential anti-adipogenic bioactive molecules. International Journal of Molecular Sciences, 17(1), 1–24. https://doi. org/10.3390/ijms17010124
74. Müller, J. C., Imazaki, P. H., Boareto, A. C., Lourenço, E. L. B., Golin, M., Vechi, M. F., … Dalsenter, P. R. (2012). In vivo and in vitro estrogen- ic activity of the antidepressant fluoxetine. Reproductive Toxicol- ogy, 34(1), 80–85. https://doi.org/10.1016/j.reprotox.2012.04.001
75. Munkboel, C. H., Larsen, L. W., Weisser, J. J., Kristensen, D. M., & Styrishave, B. (2018). Sertraline suppresses testis and adrenal steroid production and steroidogenic gene expression while increasing LH in Plasma of male rats resulting in compensatory hypogonadism. Toxicological Sciences, 163(2), 609–619. https:// doi.org/10.1093/toxsci/kfy059
76. Murphy, R., Stewart, A. W., Braithwaite, I., Beasley, R., Hancox, R. J., & Mitchell, E. A. (2015). Association between paracetamol use in infancy or childhood with body mass index. Obesity, 23(5), 1030– 1038. https://doi.org/10.1002/oby.21045
77. Newbold, R. R., Padilla-Banks, E., Jefferson, W. N., & Heindel, J. J. (2008). Effects of endocrine disruptors on obesity. International Journal of Andrology, 31(2), 201–207. https://doi.org/10.1111/ j.1365-2605.2007.00858.x
78. Newbold, R. R., Padilla-banks, E., Snyder, R. J., & Jefferson, W. N. (2005). Developmental Exposure to Estrogenic Compounds and Obesity. 480, 478–480. https://doi.org/10.1002/bdra.20147
79. Newbold, R. R., Padilla-Banks, E., Snyder, R. J., & Jefferson, W. N. (2007a). Perinatal exposure to environmental estrogens and the development of obesity. Molecular Nutrition and Food Research, Vol. 51, pp. 912–917. https://doi.org/10.1002/mnfr.200600259
80. Newbold, R. R., Padilla-Banks, E., Snyder, R. J., Phillips, T. M., & Jef- ferson, W. N. (2007b). Developmental exposure to endocrine dis- ruptors and the obesity epidemic. Reproductive Toxicology, Vol. 23, pp. 290–296. https://doi.org/10.1016/j.reprotox.2006.12.010
81. Obri, A., Serra, D., Herrero, L., & Mera, P. (2020). The role of epi- genetics in the development of obesity. Biochemical Pharmacol- ogy, Vol. 177, p. 113973. Elsevier Inc. https://doi.org/10.1016/j. bcp.2020.113973
82. OECD. (2012). OECD Detailed review paper on the state of the science on novel in vitro and in vivo screening and testing methods and endpoints for evaluating endocrine disruptors OECD Environment, Health and Safety Publica- tions Series on Testing and Assessment 2012 Par. Retrieved November 6, 2021, from https://www.oecd-ilibrary.org/ docserver/9789264221352-en.pdf?expires=1636196089&id=i d&accname=guest&checksum=960E616120F388C1D44E902 319C840AC
83. Palin, S. L., McTernan, P. G., Anderson, L. A., Sturdee, D. W., Bar- nett, A. H., & Kumar, S. (2003). 17β-Estradiol and anti-estrogen ICI:compound 182,780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdomi- nal adipocytes. Metabolism: Clinical and Experimental, 52(4), 383–388. https://doi.org/10.1053/meta.2003.50088
84. Palmer, J. R., Herbst, A. L., Noller, K. L., Boggs, D. A., Troisi, R., Titus- Ernstoff, L., … Hoover, R. N. (2009). Urogenital abnormalities in men exposed to diethylstilbestrol in utero: A cohort study. Envi- ronmental Health: A Global Access Science Source, 8, 37. https://doi. org/10.1186/1476-069X-8-37
85. Pedersen, S. B., Børglum, J. D., Mø11er-Pedersen, T., & Richelsen, B. (1992). Effects of in vivo estrogen treatment on adipose tissue metabolism and nuclear estrogen receptor binding in isolated rat adipocytes. Molecular and Cellular Endocrinology, 85(1–2), 13–19. https://doi.org/10.1016/0303-7207(92)90120-U
86. Peeke, P. M., & Chrousos, G. P. (1995). Hypercortisolism and Obe- sity. Annals of the New York Academy of Sciences, 771(1), 665–676. https://doi.org/10.1111/j.1749-6632.1995.tb44719.x
87. Piersma, A. H., Luijten, M., Popov, V., Tomenko, V., Altstein, M., Kagampang, F., & Schlesinger, H. (2009). Pharmaceuticals. In En- docrine-Disrupting Chemicals in Food (pp. 459–518). Elsevier Ltd. https://doi.org/10.1533/9781845695743.4.459
88. Raeder, M. B., Fernø, J., Vik-Mo, A. O., & Steen, V. M. (2006). SREBP activation by antipsychotic- and antidepressant-drugs in cul- tured human liver cells: Relevance for metabolic side-effects? Molecular and Cellular Biochemistry, 289(1–2), 167–173. https:// doi.org/10.1007/s11010-006-9160-4
89. Rask, E., Olsson, T., Söderberg, S., Andrew, R., Livingstone, D. E. W., Johnson, O., & Walker, B. R. (2001). Tissue-specific dysregula- tion of cortisol metabolism in human obesity. Journal of Clinical Endocrinology and Metabolism, 86(3), 1418–1421. https://doi. org/10.1210/jcem.86.3.7453
90. Richard, A. J., White, U., Elks, C. M., & Stephens, J. M. (2000). Adi- pose Tissue: Physiology to Metabolic Dysfunction. In Endotext. MDText.com, Inc. Retrieved from http://www.ncbi.nlm.nih.gov/ pubmed/32255578
91. Rissman, E. F., & Adli, M. (2014). Minireview: Transgenerational Epi- genetic Inheritance: Focus on Endocrine Disrupting Compounds. Endocrinology, 155(8), 2770. https://doi.org/10.1210/EN.2014-1123
92. Ritchie, H., & Max, R. (2017). Obesity - Our World in Data. Retrieved November 4, 2021, from https://ourworldindata.org/obesity
93. Romao, J. M., & Guan, L. L. (2014). Adipogenesis and Obesity. In MicroRNA in Regenerative Medicine (pp. 539–565). Elsevier Inc. https://doi.org/10.1016/B978-0-12-405544-5.00021-6
94. Rönn, M., Lind, L., Örberg, J., Kullberg, J., Söderberg, S., Larsson, A., … Lind, P. M. (2014). Bisphenol A is related to circulating lev- els of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans. Chemosphere, 112, 42–48. https://doi. org/10.1016/J.CHEMOSPHERE.2014.03.042
95. Rosen, E. D., & MacDougald, O. A. (2006). Adipocyte differentiation from the inside out. Nature Reviews Molecular Cell Biology, 7(12), 885–896. https://doi.org/10.1038/nrm2066
96. Rubin, B. S., Paranjpe, M., DaFonte, T., Schaeberle, C., Soto, A. M., Obin, M., & Greenberg, A. S. (2017). Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates ad- verse effects in female mice. Reproductive Toxicology (Elmsford, N.Y.), 68, 130–144. https://doi.org/10.1016/J.REPROTOX.2016.07.020
97. Safarinejad, M. R. (2008). Evaluation of endocrine profile and hypothalamic-pituitary-testis axis in selective serotonin reuptake inhibitor-induced male sexual dysfunction. Journal of Clinical Psychopharmacology, 28(4), 418–423. https://doi.org/10.1097/ JCP.0b013e31817e6f80
98. Sarjeant, K., & Stephens, J. M. (2012). Adipogenesis. Cold Spring Harbor Perspectives in Biology, 4(9), a008417. https://doi.org/10.1101/cshperspect.a008417
99. Schrager, S., & Potter, B. E. (2004). Diethylstilbestrol Exposure - Amer- ican Family Physician. Retrieved from www.aafp.org/afp.
100. Sharma, G., Hu, C., Brigman, J. L., Zhu, G., Hathaway, H. J., & Prossnitz, E. R. (2013). GPER deficiency in male mice results in in- sulin resistance, dyslipidemia, and a proinflammatory state. Endo- crinology, 154(11), 4136–4145. https://doi.org/10.1210/en.2013-1357
101. Sharma, G., & Prossnitz, E. R. (2017). G-protein-coupled estro- gen receptor (GPER) and sex-specific metabolic homeostasis. In Advances in Experimental Medicine and Biology. 1043, 427–453. https://doi.org/10.1007/978-3-319-70178-3_20
102. Sharma, G., & Prossnitz, E. R. (2021). Targeting the G protein-cou- pled estrogen receptor (GPER) in obesity and diabetes. Endocrine and Metabolic Science, 2, 100080. https://doi.org/10.1016/j.end- mts.2021.100080
103. Somm, E., Schwitzgebel, V. M., Toulotte, A., Cederroth, C. R., Combescure, C., Nef, S., … Hüppi, P. S. (2009). Perinatal exposure to bisphenol A alters early adipogenesis in the rat. Environmental Health Perspectives, 117(10), 1549–1555. https://doi.org/10.1289/ehp.11342
104. Stahlhut, R. W., Wijngaarden, E. van, Dye, T. D., Stephen, C., & Swan,
105. S. H. (2007). Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environmental Health Perspectives, 115(6), 876–882. https://doi.org/10.1289/EHP.9882
106. Stel, J., & Legler, J. (2015). The role of epigenetics in the latent effects of early life exposure to obesogenic endocrine disrupt- ing chemicals. Endocrinology, 156(10), 3466–3472. https://doi. org/10.1210/EN.2015-1434
107. Stger, R. (2008). Epigenetics and obesity. Pharmacogenomics, Vol. 9, pp. 1851–1860. https://doi.org/10.2217/14622416.9.12.1851
108. Tafuri, S. R. (1996). Troglitazone Enhances Differentiation, Basal Glucose Uptake, and Glut1 Protein Levels in 3T3-Ll Adipo- cytes. Retrieved from https://academic.oup.com/endo/arti- cle/137/11/4706/2499032
109. USEPA. (2021). What is the Endocrine System? | US EPA. Retrieved November 6, 2021, from https://www.epa.gov/endocrine-dis- ruption/what-endocrine-system
110. Verhaegen, A. A., & Van Gaal, L. F. (2017). Drug-induced obesity and its metabolic consequences: a review with a focus on mech- anisms and possible therapeutic options. Journal of Endocrino- logical Investigation, 40(11), 1165–1174. https://doi.org/10.1007/ s40618-017-0719-6
111. Vernon, R. G., & David J. Flint. (2011). Adipose tissue. Journal Fur Asthetische Chirurgie, 4(1), 28–34. https://doi.org/10.1007/s12631- 010-0116-x
112. Wake, D. J., Rask, E., Livingstone, D. E. W., So¨derberg, S., So¨derberg, S., Olsson, T., & Walker, B. R. (2003). COMMENT Local and Systemic Impact of Transcriptional Up-Regulation of 11-Hydroxysteroid Dehy- drogenase Type 1 in Adipose Tissue in Human Obesity. https://doi. org/10.1210/jc.2003-030286
113. WHO. (2021). WHO. Retrieved May 15, 2021, from World Health Organization website: https://www.who.int/news-room/fact- sheets/detail/obesity-and-overweight
114. Wu, Z., Bucher, N. L., & Farmer, S. R. (1996). Induction of peroxi- some proliferator-activated receptor gamma during the conver- sion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Molecular and Cellular Biology, 16(8), 4128–4136. https://doi.org/10.1128/mcb.16.8.4128
115. Yang, C., Lee, H. K., Kong, A. P. S., Lim, L. L., Cai, Z., & Chung, A. C. K. (2018). Early-life exposure to endocrine disrupting chemicals as- sociates with childhood obesity. Annals of Pediatric Endocrinology and Metabolism, Vol. 23, pp. 182–195. Korean society of pediatric endocrinology. https://doi.org/10.6065/apem.2018.23.4.182
116. Yang, L.-H., Chen, T.-M., Yu, S.-T., & Chen, Y.-H. (2007). Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. Pharma- cological Research, 56(3), 202–208. https://doi.org/10.1016/J. PHRS.2007.05.007
117. Zhu, P., Yuen, J. M. L., Sham, K. W. Y., & Cheng, C. H. K. (2013). GPER mediates the inhibitory actions of estrogen on adipogenesis in 3T3-L1 cells through perturbation of mitotic clonal expansion. General and Comparative Endocrinology, 193, 19–26. https://doi. org/10.1016/j.ygcen.2013.07.004