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Transgenerational effects of maternal bisphenol: a exposure on offspring metabolic health

Part of: DOHaD on International Women's Day 2020

Published online by Cambridge University Press:  26 October 2018

A. Bansal Open the ORCID record for A. Bansal [Opens in a new window] ,
C. Li ,
F. Xin ,
A. Duemler ,
W. Li ,
C. Rashid ,
M. S. Bartolomei  and
R. A. Simmons
A. Bansal
Affiliation:
Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
C. Li
Affiliation:
Division of Endocrinology and Metabolism Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
F. Xin
Affiliation:
Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
A. Duemler
Affiliation:
Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Eberly College of Science, Pennsylvania State University, University Park, PA, USA
W. Li
Affiliation:
Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
C. Rashid
Affiliation:
Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
M. S. Bartolomei
Affiliation:
Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
R. A. Simmons*
Affiliation:
Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Division of Neonatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
*
*Address for correspondence: Rebecca Simmons, MD, Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, 1308 BRB II/III, Philadelphia, PA 19104, USA. E-mails: [email protected] or [email protected]
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Abstract

Exposure to the endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with health abnormalities that persist in subsequent generations. However, transgenerational effects of BPA on metabolic health are not widely studied. In a maternal C57BL/6J mice (F0) exposure model using BPA doses that are relevant to human exposure levels (10 μg/kg/day, LowerB; 10 mg/kg/day, UpperB), we showed male- and dose-specific effects on pancreatic islets of the first (F1) and second generation (F2) offspring relative to controls (7% corn oil diet; control). In this study, we determined the transgenerational effects (F3) of BPA on metabolic health and pancreatic islets in our model. Adult F3 LowerB and UpperB male offspring had increased body weight relative to Controls, however glucose tolerance was similar in the three groups. F3 LowerB, but not UpperB, males had reduced β-cell mass and smaller islets which was associated with increased glucose-stimulated insulin secretion. Similar to F1 and F2 BPA male offspring, staining for markers of T-cells and macrophages (CD3 and F4/80) was increased in pancreas of F3 LowerB and UpperB male offspring, which was associated with changes in cytokine levels. In contrast to F3 BPA males, LowerB and UpperB female offspring had comparable body weight, glucose tolerance and insulin secretion as Controls. Thus, maternal BPA exposure resulted in fewer metabolic defects in F3 than F1 and F2 offspring, and these were sex- and dose-specific.

Keywords

β-cell massendocrine disruptorsinflammationinsulin secretionisletstransgenerational
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 10 , Issue 2 , April 2019 , pp. 164 - 175
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018. 

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Footnotes

The online version of this article has been updated since original publication. A notice detailing the changes has also been published at doi: 10.1017/S2040174418000934

References

1. Gore, AC, Chappell, VA, Fenton, SE, et al. EDC-2: The Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev . 2015; 36, E1–E150. https://doi.org/10.1210/er.2015-1010. Epub 2015 Nov 6.Google Scholar
2. Kavlock, RJ, Daston, GP, DeRosa, C, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Perspect. 1996; 104(Suppl 4), 715–740.Google Scholar
3. Zoeller, RT, Brown, TR, Doan, LL, et al. Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology. 2012; 153, 4097–4110, https://doi.org/10.1210/en.2012-1422. Epub 2012 Jun 25.Google Scholar
4. Stahlhut, RW, Welshons, WV, Swan, SH. Bisphenol A data in NHANES suggest longer than expected half-life, substantial nonfood exposure, or both. Environ Health Perspect. 2009; 117, 784–789.Google Scholar
5. Shankar, A, Teppala, S. Relationship between urinary bisphenol A levels and diabetes mellitus. J Clin Endocrinol Metab. 2011; 96, 3822–3826, https://doi.org/10.1210/jc.2011-1682. Epub 2011 Sep 28.Google Scholar
6. Sabanayagam, C, Teppala, S, Shankar, A. Relationship between urinary bisphenol A levels and prediabetes among subjects free of diabetes. Acta Diabetol. 2013; 50, 625–631, https://doi.org/10.1007/s00592-013-0472-z. Epub 2013 May 1.Google Scholar
7. Ahmadkhaniha, R, Mansouri, M, Yunesian, M, et al. Association of urinary bisphenol a concentration with type-2 diabetes mellitus. J Environ Health Sci Eng. 2014; 12, 64, https://doi.org/10.1186/2052-336X-12-64.Google Scholar
8. Aekplakorn, W, Chailurkit, LO, Ongphiphadhanakul, B. Relationship of serum bisphenol A with diabetes in the Thai population, National Health Examination Survey IV, 2009. J Diabetes. 2015; 7, 240–249, https://doi.org/10.1111/753-0407.12159. Epub 2014 May 8.Google Scholar
9. Sun, Q, Cornelis, MC, Townsend, MK, et al. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII cohorts. Environ Health Perspect. 2014; 122, 616–623, https://doi.org/10.1289/ehp.1307201. Epub 2014 Mar 14.Google Scholar
10. Batista, TM, Alonso-Magdalena, P, Vieira, E, et al. Short-term treatment with bisphenol-A leads to metabolic abnormalities in adult male mice. PLoS One. 2012; 7, e33814, https://doi.org/10.1371/journal.pone.0033814. Epub 2012 Mar 28.Google Scholar
11. Alonso-Magdalena, P, Morimoto, S, Ripoll, C, Fuentes, E, Nadal, A. The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environ Health Perspect. 2006; 114, 106–112.Google Scholar
12. Anway, MD, Cupp, AS, Uzumcu, M, Skinner, MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308, 1466–1469.Google Scholar
13. Crews, D, Gore, AC, Hsu, TS, et al. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci U S A. 2007; 104, 5942–5946, Epub 2007 Mar 26.Google Scholar
14. Anway, MD, Skinner, MK. Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. Prostate. 2008; 68, 517–529. https://doi.org/10.1002/pros.20724.Google Scholar
15. Salian, S, Doshi, T, Vanage, G. Impairment in protein expression profile of testicular steroid receptor coregulators in male rat offspring perinatally exposed to Bisphenol A. Life Sci. 2009; 85, 11–18. https://doi.org/10.1016/j.lfs.2009.04.005. Epub Apr 18.Google Scholar
16. Guerrero-Bosagna, C, Settles, M, Lucker, B, Skinner, MK. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One. 2010; 5, (pii): e13100. https://doi.org/10.1371/journal.pone.0013100.Google Scholar
17. Wolstenholme, JT, Goldsby, JA, Rissman, EF. Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav. 2013; 64, 833–839. https://doi.org/10.1016/j.yhbeh.2013.09.007. Epub Oct 5.Google Scholar
18. Bhandari, RK, vom Saal, FS, Tillitt, DE. Transgenerational effects from early developmental exposures to bisphenol A or 17alpha-ethinylestradiol in medaka, Oryzias latipes . Sci Rep. 2015; 5, 9303. https://doi.org/10.1038/srep09303.Google Scholar
19. Goldsby, JA, Wolstenholme, JT, Rissman, EF. Multi- and transgenerational consequences of bisphenol A on sexually dimorphic cell populations in mouse brain. Endocrinology. 2017; 158, 21–30. https://doi.org/10.1210/en.2016-1188.Google Scholar
20. Derouiche, L, Keller, M, Duittoz, AH, Pillon, D. Developmental exposure to Ethinylestradiol affects transgenerationally sexual behavior and neuroendocrine networks in male mice. Sci Rep. 2015; 5, 17457. https://doi.org/10.1038/srep17457.Google Scholar
21. Lombo, M, Fernandez-Diez, C, Gonzalez-Rojo, S, et al. Transgenerational inheritance of heart disorders caused by paternal bisphenol A exposure. Environ Pollut. 2015; 206, 667–678, https://doi.org/10.1016/j.envpol.2015.08.016. Epub Aug 31.Google Scholar
22. Wolstenholme, JT, Edwards, M, Shetty, SR, et al. Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology. 2012; 153, 3828–3838, https://doi.org/10.1210/en.2012-1195. Epub 2012 Jun 15.Google Scholar
23. Drobna, Z, Henriksen, AD, Wolstenholme, JT, et al. Transgenerational effects of bisphenol A on gene expression and DNA methylation of imprinted genes in brain. Endocrinology. 2018; 159, 132–144, https://doi.org/10.1210/en.2017-00730.Google Scholar
24. 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, e55387, https://doi.org/10.1371/journal.pone.0055387. Epub 2013 Jan 24.Google Scholar
25. Susiarjo, M, Xin, F, Bansal, A, et al. Bisphenol a exposure disrupts metabolic health across multiple generations in the mouse. Endocrinology. 2015; 156, 2049–2058.Google Scholar
26. Bansal, A, Rashid, C, Xin, F, et al. Sex- and dose-specific effects of maternal bisphenol A exposure on pancreatic islets of first and second generation adult mice offspring. Environ Health Perspect. 2017; 125, 0970221–09702218.Google Scholar
27. Dolinoy, DC, Huang, D, Jirtle, RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A . 2007; 104, 13056–13061, https://doi.org/10.1073/pnas.0703739104. Epub 2007 Aug 1.Google Scholar
28. Susiarjo, M, Sasson, I, Mesaros, C, Bartolomei, MS. Bisphenol a exposure disrupts genomic imprinting in the mouse. PLoS Genet. 2013; 9, e1003401, https://doi.org/10.1371/journal.pgen. Epub 2013 Apr 4.Google Scholar
29. Integrated Risk Information System (IRIS). Bisphenol A (CASRN 80-05-7). 1988.Google Scholar
30. Schonfelder, G, Wittfoht, W, Hopp, H, et al. Parent bisphenol A accumulation in the human maternal-fetal-placental unit. Environ Health Perspect. 2002; 110, A703–A707.Google Scholar
31. Vandenberg, LN, Hauser, R, Marcus, M, Olea, N, Welshons, WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007; 24, 139–177, https://doi.org/10.1016/j.reprotox.2007.07.010. Epub Jul 31.Google Scholar
32. Scaglia, L, Smith, FE, Bonner-Weir, S. Apoptosis contributes to the involution of beta cell mass in the post partum rat pancreas. Endocrinology. 1995; 136, 5461–5468.Google Scholar
33. Scaglia, L, Cahill, CJ, Finegood, DT, Bonner-Weir, S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology. 1997; 138, 1736–1741.Google Scholar
34. Finegood, DT, Scaglia, L, Bonner-Weir, S. Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes. 1995; 44, 249–256.Google Scholar
35. Swenne, I. Effects of aging on the regenerative capacity of the pancreatic B-cell of the rat. Diabetes. 1983; 32, 14–19.Google Scholar
36. Chen, W, Wilson, JL, Khaksari, M, Cowley, MA, Enriori, PJ. Abdominal fat analyzed by DEXA scan reflects visceral body fat and improves the phenotype description and the assessment of metabolic risk in mice. Am J Physiol Endocrinol Metab. 2012; 303, E635–E643, https://doi.org/10.1152/ajpendo.00078.2012. Epub 2012 Jul 3.Google Scholar
37. Li, C, Chen, P, Palladino, A, et al. Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem. 2010; 285, 31806–31818, https://doi.org/10.1074/jbc.M110.123638. Epub 2010 Jul 29.Google Scholar
38. Jaeckle Santos, LJ, Li, C, Doulias, PT, et al. Neutralizing Th2 inflammation in neonatal islets prevents beta-cell failure in adult IUGR rats. Diabetes. 2014; 63, 1672–1684, https://doi.org/10.2337/db13-1226. Epub 2014 Jan 9.Google Scholar
39. Jansen, A, Voorbij, HA, Jeucken, PH, et al. An immunohistochemical study on organized lymphoid cell infiltrates in fetal and neonatal pancreases. A comparison with similar infiltrates found in the pancreas of a diabetic infant. Autoimmunity. 1993; 15, 31–38.Google Scholar
40. Jansen, A, Homo-Delarche, F, Hooijkaas, H, et al. Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice. Diabetes. 1994; 43, 667–675.Google Scholar
41. Geutskens, SB, Otonkoski, T, Pulkkinen, MA, Drexhage, HA, Leenen, PJ. Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro. J Leukoc Biol. 2005; 78, 845–852, Epub 2005 Jul 21.Google Scholar
42. Criscimanna, A, Coudriet, GM, Gittes, GK, Piganelli, JD, Esni, F. Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and beta-cell regeneration in mice. Gastroenterology. 2014; 147, 1106–1118.e11, https://doi.org/10.053/j.gastro.2014.08.008. Epub Aug 14.Google Scholar
43. Banaei-Bouchareb, L, Gouon-Evans, V, Samara-Boustani, D, et al. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J Leukoc Biol. 2004; 76, 359–367, Epub 2004 Jun 3.Google Scholar
44. Brown, ML, Schneyer, AL. Emerging roles for the TGFbeta family in pancreatic beta-cell homeostasis. Trends Endocrinol Metab. 2010; 21, 441–448, https://doi.org/10.1016/j.tem.2010.02.008. Epub Apr 8.Google Scholar
45. Han, B, Qi, S, Hu, B, Luo, H, Wu, J. TGF-beta i promotes islet beta-cell function and regeneration. J Immunol. 2011; 186, 5833–5844, https://doi.org/10.4049/jimmunol.1002303. Epub 2011 Apr 6.Google Scholar
46. Lin, HM, Lee, JH, Yadav, H, et al. Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem. 2009; 284, 12246–12257, https://doi.org/10.1074/jbc.M805379200. Epub 2009 Mar 5.Google Scholar
47. Lehmann, R, Zuellig, RA, Kugelmeier, P, et al. Superiority of small islets in human islet transplantation. Diabetes. 2007; 56, 594–603.Google Scholar
48. MacGregor, RR, Williams, SJ, Tong, PY, et al. Small rat islets are superior to large islets in in vitro function and in transplantation outcomes. Am J Physiol Endocrinol Metab. 2006; 290, E771–E779.Google Scholar
49. Martin, F, Andreu, E, Rovira, JM, et al. Mechanisms of glucose hypersensitivity in beta-cells from normoglycemic, partially pancreatectomized mice. Diabetes. 1999; 48, 1954–1961.Google Scholar
50. Leahy, JL, Bumbalo, LM, Chen, C. Beta-cell hypersensitivity for glucose precedes loss of glucose-induced insulin secretion in 90% pancreatectomized rats. Diabetologia. 1993; 36, 1238–1244.Google Scholar
51. Nolan, CJ, Delghingaro-Augusto, V. Reversibility of defects in proinsulin processing and islet beta-cell failure in obesity-related type 2 diabetes. Diabetes. 2016; 65, 352–354, https://doi.org/10.2337/dbi15-0020.Google Scholar
52. Fridlyand, LE, Philipson, LH. Does the glucose-dependent insulin secretion mechanism itself cause oxidative stress in pancreatic beta-cells? Diabetes. 2004; 53, 1942–1948.Google Scholar
53. Ding, S, Fan, Y, Zhao, N, et al. High-fat diet aggravates glucose homeostasis disorder caused by chronic exposure to bisphenol A. J Endocrinol. 2014; 221, 167–179, https://doi.org/10.1530/JOE-13-0386. Print 2014 Apr.Google Scholar
54. Leung, YK, Govindarajah, V, Cheong, A, et al. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk. Endocr Relat Cancer. 2017; 24, 365–378, https://doi.org/10.1530/ERC-17-0006. Epub 2017 May 9.Google Scholar
55. Tarapore, P, Hennessy, M, Song, D, et al. High butter-fat diet and bisphenol A additively impair male rat spermatogenesis. Reprod Toxicol. 2017; 68, 191–199, https://doi.org/10.1016/j.reprotox.2016.09.008. Epub Sep 19.Google Scholar
56. Strakovsky, RS, Wang, H, Engeseth, NJ, et al. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicol Appl Pharmacol. 2015; 284, 101–112, https://doi.org/10.1016/j.taap.2015.02.021. Epub Mar 5.Google Scholar
57. Morris, DL. Minireview: emerging concepts in islet macrophage biology in type 2 diabetes. Mol Endocrinol. 2015; 29, 946–962, https://doi.org/10.1210/me.2014-1393. Epub 2015 May 22.Google Scholar
58. Maedler, K, Sergeev, P, Ris, F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002; 110, 851–860.Google Scholar
59. Taylor-Fishwick, DA, Weaver, JR, Grzesik, W, et al. Production and function of IL-12 in islets and beta cells. Diabetologia. 2013; 56, 126–135, https://doi.org/10.1007/s00125-012-2732-9. Epub 2012 Oct 3.Google Scholar
60. Chamorro-Garcia, R, Diaz-Castillo, C, Shoucri, BM, et al. Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice. Nat Commun. 2017; 8, 2012, https://doi.org/10.1038/s41467-017-01944-z.Google Scholar
61. Skinner, MK, Manikkam, M, Tracey, R, et al. Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity. BMC Med. 2013; 11, 228, https://doi.org/10.1186/741-7015-11-228.Google Scholar
62. Roseboom, T, de Rooij, S, Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006; 82, 485–491, Epub 2006 Jul 28.Google Scholar
63. Ravelli, AC, van Der Meulen, JH, Osmond, C, Barker, DJ, Bleker, OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr. 1999; 70, 811–816.Google Scholar
64. Arendas, K, Qiu, Q, Gruslin, A. Obesity in pregnancy: pre-conceptional to postpartum consequences. J Obstet Gynaecol Can. 2008; 30, 477–488.Google Scholar
65. Lof, M, Hilakivi-Clarke, L, Sandin, S, Weiderpass, E. Effects of pre-pregnancy physical activity and maternal BMI on gestational weight gain and birth weight. Acta Obstet Gynecol Scand. 2008; 87, 524–530, https://doi.org/10.1080/00016340802012288.Google Scholar
66. Whitehead, N, Lipscomb, L. Patterns of alcohol use before and during pregnancy and the risk of small-for-gestational-age birth. Am J Epidemiol. 2003; 158, 654–662.Google Scholar
67. Weisman, CS, Misra, DP, Hillemeier, MM, et al. Preconception predictors of birth outcomes: prospective findings from the central Pennsylvania women’s health study. Matern Child Health J. 2011; 15, 829–835, https://doi.org/10.1007/s10995-009-0473-2. Epub 2009 May 27.Google Scholar
68. Catalano, P, deMouzon, SH. Maternal obesity and metabolic risk to the offspring: why lifestyle interventions may have not achieved the desired outcomes. Int J Obes (Lond). 2015; 39, 642–649, https://doi.org/10.1038/ijo.2015.15. Epub Jan 5.Google Scholar
69. Oliver, MH, Hawkins, P, Harding, JE. Periconceptional undernutrition alters growth trajectory and metabolic and endocrine responses to fasting in late-gestation fetal sheep. Pediatr Res. 2005; 57, 591–598, Epub 2005 Feb 4.Google Scholar
70. Rumball, CW, Bloomfield, FH, Oliver, MH, Harding, JE. Different periods of periconceptional undernutrition have different effects on growth, metabolic and endocrine status in fetal sheep. Pediatr Res. 2009; 66, 605–613, https://doi.org/10.1203/PDR.0b013e3181bbde72.Google Scholar
71. Stevens, A, Begum, G, Cook, A, et al. Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology. 2010; 151, 3652–3664, https://doi.org/10.1210/en.2010-0094. Epub 2010 Jun 23.Google Scholar
72. Turner, MD, Nedjai, B, Hurst, T, Pennington, DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014; 1843, 2563–2582, https://doi.org/10.1016/j.bbamcr.2014.05.014. Epub Jun 2.Google Scholar
73. Kourilsky, P, Truffa-Bachi, P. Cytokine fields and the polarization of the immune response. Trends Immunol. 2001; 22, 502–509.Google Scholar
74. Commins, SP, Borish, L, Steinke, JW. Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol. 2010; 125(2 Suppl 2), S53–S72, https://doi.org/10.1016/j.jaci.2009.07.008. Epub Nov 24.Google Scholar
75. Cavaillon, JM. Pro-versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol (Noisy-le-grand). 2001; 47, 695–702.Google Scholar
76. Kimura, A, Kishimoto, T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010; 40, 1830–1835, https://doi.org/10.002/eji.201040391.Google Scholar
77. Gee, K, Guzzo, C, Che Mat, NF, Ma, W, Kumar, A. The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets. 2009; 8, 40–52.Google Scholar
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