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Enriched Environment Decelerates the Development of Endometriosis in Mouse

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Abstract

We tested the hypothesis that enriched environment (EE), consisting of enlarged space, and increased physical activity and social interactions, hinders the development of endometriosis through attenuated adrenergic signaling, enhanced autophagy, and reduced leptin levels. Two mouse experiments were performed. In Experiment 1, 40 female Balb/C mice were randomly divided into four equal-sized groups, the SE (standard environment), EE, p-EE (EE instituted after endometriosis induction), and the d-EE (SE housing but received uterine fragments from EE donors) groups. Housing intervention was initiated 3 weeks before the induction of endometriosis and continued for 3 weeks after induction. In Experiment 2, 20 female mice were randomly divided into SE and EE groups, and the plasma leptin levels were measured. We measured lesion weight and hotplate latency and performed Masson trichrome staining as well as immunohistochemistry analysis of β2 adrenergic receptor (ADRB2), dopamine receptor D2 (DRD2), vascular endothelial growth factor (VEGF), and microtubule-associated protein light chain 3 (LC3). We found that EE reduced the lesion weight by 40.8% as compared with SE mice, but the reduction in p-EE and d-EE mice did not reach statistical significance. EE significantly reduced staining levels of ADRB2 and VEGF as well as the extent of lesional fibrosis but increased staining levels of LC3 and DRD2 in lesions as compared with the SE group. EE mice had reduced plasma leptin levels as compared with SE mice. Thus, EE decelerates the development of endometriosis and fibrogenesis and improved generalized hyperalgesia, possibly through increased DRD2 expression but decreased expression of ADRB2 and VEGF as well as enhanced autophagy and reduced leptin level.

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References

  1. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10:261–75.

    Article  CAS  PubMed  Google Scholar 

  2. Lagana AS, La Rosa VL, Rapisarda AMC, Valenti G, Sapia F, Chiofalo B, et al. Anxiety and depression in patients with endometriosis: impact and management challenges. Int J Women's Health. 2017;9:323–30.

    Article  Google Scholar 

  3. Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18:177–200.

    Article  PubMed  Google Scholar 

  4. Barnack JL, Chrisler JC. The experience of chronic illness in women: a comparison between women with endometriosis and women with chronic migraine headaches. Women Health. 2007;46:115–33.

    Article  PubMed  Google Scholar 

  5. Eriksen HL, Gunnersen KF, Sorensen JA, Munk T, Nielsen T, Knudsen UB. Psychological aspects of endometriosis: differences between patients with or without pain on four psychological variables. Eur J Obstet Gynecol Reprod Biol. 2008;139:100–5.

    Article  PubMed  Google Scholar 

  6. Quinones M, Urrutia R, Torres-Reveron A, Vincent K, Flores I. Anxiety, coping skills and hypothalamus-pituitary-adrenal (HPA) axis in patients with endometriosis. J Reprod Biol Health. 2015;3:2.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Li T, Mamillapalli R, Ding S, Chang H, Liu ZW, Gao XB, et al. Endometriosis alters brain electro-physiology, gene expression and increased pain sensitization, anxiety, and depression in female mice. Biol Reprod. 2018;99:349–59.

  8. Cuevas M, Flores I, Thompson KJ, Ramos-Ortolaza DL, Torres-Reveron A, Appleyard CB. Stress exacerbates endometriosis manifestations and inflammatory parameters in an animal model. Reprod Sci. 2012;19:851–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Appleyard CB, Cruz ML, Hernandez S, Thompson KJ, Bayona M, Flores I. Stress management affects outcomes in the pathophysiology of an endometriosis model. Reprod Sci. 2015;22:431–41.

    Article  CAS  PubMed  Google Scholar 

  10. Hernandez S, Cruz ML, Seguinot II, Torres-Reveron A, Appleyard CB. Impact of psychological stress on pain perception in an animal model of endometriosis. Reprod Sci. 2017;24:1371–81.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cuevas M, Cruz ML, Ramirez AE, Flores I, Thompson KJ, Bayona M, et al. Stress during development of experimental endometriosis influences nerve growth and disease progression. Reprod Sci. 2018;25:347–57.

    Article  CAS  PubMed  Google Scholar 

  12. Guo SW, Zhang Q, Liu X. Social psychogenic stress promotes the development of endometriosis in mouse. Reprod BioMed Online. 2017;34:225–39.

    Article  PubMed  Google Scholar 

  13. Long Q, Liu X, Qi Q, Guo SW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor beta2. Hum Reprod. 2016;31:2506–19.

    Article  CAS  PubMed  Google Scholar 

  14. Slater AM, Cao L. A protocol for housing mice in an enriched environment. J Visual Exp : JoVE 2015:e52874.

  15. Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006;7:697–709.

    Article  CAS  PubMed  Google Scholar 

  16. Baldini S, Restani L, Baroncelli L, Coltelli M, Franco R, Cenni MC, et al. Enriched early life experiences reduce adult anxiety-like behavior in rats: a role for insulin-like growth factor 1. J Neurosci. 2013;33:11715–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, Tsien JZ. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat Neurosci. 2000;3:238–44.

    Article  CAS  PubMed  Google Scholar 

  18. Sale A, Berardi N, Maffei L. Enrich the environment to empower the brain. Trends Neurosci. 2009;32:233–9.

    Article  CAS  PubMed  Google Scholar 

  19. Cao L, Liu X, Lin EJ, Wang C, Choi EY, Riban V, et al. Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell. 2010;142:52–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li G, Gan Y, Fan Y, Wu Y, Lin H, Song Y, et al. Enriched environment inhibits mouse pancreatic cancer growth and down-regulates the expression of mitochondria-related genes in cancer cells. Sci Rep. 2015;5:7856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nachat-Kappes R, Pinel A, Combe K, Lamas B, Farges MC, Rossary A, et al. Effects of enriched environment on COX-2, leptin and eicosanoids in a mouse model of breast cancer. PLoS One. 2012;7:e51525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Torres-Reveron A, Rivera LL, Flores I, Appleyard CB. Environmental manipulations as an effective alternative treatment to reduce endometriosis progression. Reprod Sci. 2018;25:1336–48.

    Article  CAS  PubMed  Google Scholar 

  23. Andreollo NA, Santos EF, Araujo MR, Lopes LR. Rat's age versus human's age: what is the relationship? Arq Bras Cir Dig. 2012;25:49–51.

    Article  PubMed  Google Scholar 

  24. Quinn R. Comparing rat's to human's age: how old is my rat in people years? Nutrition. 2005;21:775–7.

    Article  PubMed  Google Scholar 

  25. Zhang Q, Duan J, Liu X, Guo SW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol. 2016;428:1–16.

    Article  PubMed  CAS  Google Scholar 

  26. Zhang Q, Duan J, Olson M, Fazleabas A, Guo SW. Cellular changes consistent with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the progression of experimental endometriosis in baboons. Reprod Sci. 2016;23:1409–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo SW. Fibrogenesis resulting from cyclic bleeding: the holy grail of the natural history of ectopic endometrium. Hum Reprod. 2018.

  28. Torres-Reveron A, Palermo K, Hernandez-Lopez A, Hernandez S, Cruz ML, Thompson KJ, et al. Endometriosis is associated with a shift in MU opioid and NMDA receptor expression in the brain periaqueductal gray. Reprod Sci. 2016;23:1158–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cao L, Choi EY, Liu X, Martin A, Wang C, Xu X, et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab. 2011;14:324–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Choi SS, Syn WK, Karaca GF, Omenetti A, Moylan CA, Witek RP, et al. Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway. J Biol Chem. 2010;285:36551–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jain M, Budinger GR, Lo A, Urich D, Rivera SE, Ghosh AK, et al. Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-gamma. Am J Respir Crit Care Med. 2011;183:1490–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, et al. Autophagy in idiopathic pulmonary fibrosis. PLoS One. 2012;7:e41394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2013;304:L56–69.

    Article  CAS  PubMed  Google Scholar 

  34. National Research Council. Guide for the care and use of laboratory animals. Washington: National Academies Press; 1996.

  35. Sztainberg Y, Chen A. An environmental enrichment model for mice. Nat Protoc. 2010;5:1535–9.

    Article  CAS  PubMed  Google Scholar 

  36. Bacci M, Capobianco A, Monno A, Cottone L, Di Puppo F, Camisa B, et al. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. Am J Pathol. 2009;175:547–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Long Q, Liu X, Guo SW. Surgery accelerates the development of endometriosis in mice. Am J Obstet Gynecol. 2016;215:320 e1–e15.

    Article  Google Scholar 

  38. Shen M, Liu X, Zhang H, Guo SW. Transforming growth factor beta1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum Reprod. 2016;31:355–69.

    Article  CAS  PubMed  Google Scholar 

  39. Guo SW, Ding D, Geng JG, Wang L, Liu X. P-selectin as a potential therapeutic target for endometriosis. Fertil Steril. 2015;103:990–1000 e8.

    Article  CAS  PubMed  Google Scholar 

  40. Zhu B, Chen Y, Zhang H, Liu X, Guo SW. Resveratrol reduces myometrial infiltration, uterine hyperactivity, and stress levels and alleviates generalized hyperalgesia in mice with induced adenomyosis. Reprod Sci. 2015;22:1336–49.

    Article  CAS  PubMed  Google Scholar 

  41. Satoh J, Motohashi N, Kino Y, Ishida T, Yagishita S, Jinnai K, et al. LC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains. Orphanet J Rare Diseases. 2014;9:68.

    Article  Google Scholar 

  42. Wisely EV, Xiang YK, Oddo S. Genetic suppression of beta2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. Hum Mol Genet. 2014;23:4024–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cox CJ, Sharma M, Leckman JF, Zuccolo J, Zuccolo A, Kovoor A, et al. Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease. J Immunol (Baltimore, Md : 1950). 2013;191:5524–41.

    Article  CAS  Google Scholar 

  44. Liu X, Zhang Q, Guo SW. Histological and immunohistochemical characterization of the similarity and difference between ovarian endometriomas and deep infiltrating endometriosis. Reprod Sci. 2018;25:329–40.

    Article  PubMed  Google Scholar 

  45. Zhang Q, Liu X, Guo SW. Progressive development of endometriosis and its hindrance by anti-platelet treatment in mice with induced endometriosis. Reprod BioMed Online. 2017;34:124–36.

    Article  CAS  PubMed  Google Scholar 

  46. R Core Team (2019). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.

  47. Phillips-Farfan BV, Rubio Osornio M del C, Custodio Ramirez V, Paz Tres C, Carvajal Aguilera KG. Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway. Front Cell Neurosci. 2015;9:90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Yin B, Liu X, Guo SW. Caloric restriction dramatically stalls lesion growth in mice with induced endometriosis. Reprod Sci. 2018;25:1024–36.

  49. Cao Y, Liu X, Guo SW. Plasma high mobility group box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA) as admissible biomarkers for endometriosis. Sci Rep. 2019;9:9272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Torres-Reveron A, Rivera-Lopez LL, Flores I, Appleyard CB. Antagonizing the corticotropin releasing hormone receptor 1 with antalarmin reduces the progression of endometriosis. PLoS One. 2018;13:e0197698.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 2016;23:554–62.

    Article  CAS  PubMed  Google Scholar 

  52. Bonocher CM, Montenegro ML, Rosa ESJC, Ferriani RA, Meola J. Endometriosis and physical exercises: a systematic review. Reprod Biol Endocrinol. 2014;12:4.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ricci E, Vigano P, Cipriani S, Chiaffarino F, Bianchi S, Rebonato G, et al. Physical activity and endometriosis risk in women with infertility or pain: systematic review and meta-analysis. Medicine (Baltimore). 2017;95:e4957.

    Article  Google Scholar 

  54. Toth B. Stress, inflammation and endometriosis: are patients stuck between a rock and a hard place? J Mol Med (Berl). 2010;88:223–5.

    Article  Google Scholar 

  55. Moncek F, Duncko R, Johansson BB, Jezova D. Effect of environmental enrichment on stress related systems in rats. J Neuroendocrinol. 2004;16:423–31.

    Article  CAS  PubMed  Google Scholar 

  56. Li S, Jin M, Zhang D, Yang T, Koeglsperger T, Fu H, et al. Environmental novelty activates beta2-adrenergic signaling to prevent the impairment of hippocampal LTP by Abeta oligomers. Neuron. 2013;77:929–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Song Y, Gan Y, Wang Q, Meng Z, Li G, Shen Y, et al. Enriching the housing environment for mice enhances their NK cell antitumor immunity via sympathetic nerve-dependent regulation of NKG2D and CCR5. Cancer Res. 2017;77:1611–22.

    Article  CAS  PubMed  Google Scholar 

  58. Alviggi C, Clarizia R, Castaldo G, Matarese G, Colucci CC, Conforti S, et al. Leptin concentrations in the peritoneal fluid of women with ovarian endometriosis are different according to the presence of a 'deep' or 'superficial' ovarian disease. Gynecol Endocrinol. 2009;25:610–5.

    Article  CAS  PubMed  Google Scholar 

  59. Barcz E, Milewski L, Radomski D, Dziunycz P, Kaminski P, Roszkowski PI, et al. A relationship between increased peritoneal leptin levels and infertility in endometriosis. Gynecol Endocrinol. 2008;24:526–30.

    Article  CAS  PubMed  Google Scholar 

  60. Choi YS, Oh HK, Choi JH. Expression of adiponectin, leptin, and their receptors in ovarian endometrioma. Fertil Steril. 2013;100:135–41 e1–2.

    Article  CAS  PubMed  Google Scholar 

  61. Oh HK, Choi YS, Yang YI, Kim JH, Leung PC, Choi JH. Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Mol Hum Reprod. 2013;19:160–8.

    Article  CAS  PubMed  Google Scholar 

  62. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1–222.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Choi J, Jo M, Lee E, Kim HJ, Choi D. Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts. Mol Hum Reprod. 2014;20:309–17.

    Article  CAS  PubMed  Google Scholar 

  65. Yin X, Pavone ME, Lu Z, Wei J, Kim JJ. Increased activation of the PI3K/AKT pathway compromises decidualization of stromal cells from endometriosis. J Clin Endocrinol Metab. 2012;97:E35–43.

    Article  CAS  PubMed  Google Scholar 

  66. Sui X, Li Y, Sun Y, Li C, Li X, Zhang G. Expression and significance of autophagy genes LC3, Beclin1 and MMP-2 in endometriosis. Exp Ther Med. 2018;16:1958–62.

    PubMed  PubMed Central  Google Scholar 

  67. Choi J, Jo M, Lee E, Lee DY, Choi D. Dienogest enhances autophagy induction in endometriotic cells by impairing activation of AKT, ERK1/2, and mTOR. Fertil Steril. 2015;104:655–64 e1.

    Article  CAS  PubMed  Google Scholar 

  68. Shi J, Shi S, Wu B, Zhang J, Li Y, Wu X, et al. Autophagy protein LC3 regulates the fibrosis of hypertrophic scar by controlling Bcl-xL in dermal fibroblasts. Oncotarget. 2017;8:93757–70.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Xiao R, Bergin SM, Huang W, Slater AM, Liu X, Judd RT, et al. Environmental and genetic activation of hypothalamic BDNF modulates T-cell immunity to exert an anticancer phenotype. Cancer Immunol Res. 2016;4:488–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Goncalves AV, Barros NF, Bahamondes L. The practice of hatha yoga for the treatment of pain associated with endometriosis. J Altern Complement Med. 2017;23:45–52.

    Article  PubMed  Google Scholar 

  71. Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, Wilf A, et al. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci. 2004;20:1341–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank two anonymous reviewers for their constructive comments and suggestions on an earlier version of this manuscript.

Funding

This research was supported in part by grants 81530040 (SWG), 81771553 (SWG), and 81671436 (XSL) from the National Science Foundation of China and an Excellence in Centers of Clinical Medicine grant (2017ZZ01016) from the Science and Technology Commission of Shanghai Municipality.

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  1. Bo Yin and Hongyuan Jiang contributed equally to this work.

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  1. Shanghai OB/GYN Hospital, Fudan University, Shanghai, 200011, China

    Bo Yin, Hongyuan Jiang, Xishi Liu & Sun-Wei Guo

  2. Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China

    Xishi Liu & Sun-Wei Guo

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  1. Bo Yin
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Yin, B., Jiang, H., Liu, X. et al. Enriched Environment Decelerates the Development of Endometriosis in Mouse. Reprod. Sci. 27, 1423–1435 (2020). https://doi.org/10.1007/s43032-019-00117-1

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