Review Article

The effects of early low dose exposures to the Environmental Estrogen Bisphenol A on the Development of Childhood Asthma

Terumi Midoro-Horiuti* and Randall M Goldblum

Published: 10 July, 2017 | Volume 1 - Issue 1 | Pages: 015-027

Exposure to environmental chemicals is a potential cause for the rapid increase in the prevalence of allergic asthma over the last few decades. The production of the environmental estrogen bisphenol A, the monomer of polycarbonate plastics, has increased rapidly over the last 50 years, such that bisphenol A is one of the most highly produced chemicals. It is detectable in the urine of the vast majority of the human population. While the relationship between the increase of bisphenol A in our environment and the prevalence of asthma does not prove a cause and effect relationship, it provides a strong rationale for experiments that have tested the hypothesis. Because of its small molecular size and hydrophobicity, bisphenol A is easily transferred from the mother to the fetus, via the placenta and in breast milk.

We have reviewed all the publications available on medline on the human epidemiological studies of the early bisphenol A exposure on the development of allergic asthma and experimental studies using mouse model of the effects of early bisphenol A exposure on the development of asthma. There are eight human epidemiological studies and five mouse model studies currently published.

The human studies suggest that bisphenol A exposure in early life enhances the likelihood of developing asthma on at least one of the study groups. The effects of early bisphenol A exposure were observed as an enhanced development of asthma before adolescent in the animal model.

Read Full Article HTML DOI: 10.29328/journal.haard.1001003 Cite this Article Read Full Article PDF


  1. Kahr N, Naeser V, Stensballe LG, Kyvik KO, Skytthe A, et al. Gene-environment interaction in atopic diseases: a population-based twin study of early-life exposures. Clin Respir J. 2015; 9: 79-86. Ref.: https://goo.gl/LnKi1t
  2. Bonds RS, Midoro-Horiuti T. Estrogen effects in allergy and asthma. Curr Opin Allergy Clin Immunol. 2013; 13: 92-99. Ref.: https://goo.gl/1sEYTe
  3. Ng SC, Gilman-Sachs A, Thaker P, Beaman KD, Beer AE, et al. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol. 2002; 48: 77-86. Ref.: https://goo.gl/edikvY
  4. Piccinni MP, Maggi E, Romagnani S. Role of hormone-controlled T-cell cytokines in the maintenance of pregnancy. Biochem Soc Trans. 2000; 28: 212-215. Ref.: https://goo.gl/3JnN5m
  5. Iwata M, Eshima Y, Kagechika H, Miyaura H. The endocrine disruptor’s nonylphenol and octylphenol exert direct effects on T cells to suppress Th1 development and enhance Th2 development. Immunol Lett. 2004; 94: 135-139. Ref.: https://goo.gl/gEpexT
  6. Yan H, Takamoto M, Sugane K. Exposure to Bisphenol A prenatally or in adulthood promotes T (H) 2 cytokine production associated with reduction of CD4CD25 regulatory T cells. Environ Health Perspect. 2008; 116: 514-519. Ref.: https://goo.gl/AQ3REY
  7. Cai Y, Zhou J, Webb DC. Estrogen stimulates Th2 cytokine production and regulates the compartmentalisation of eosinophils during allergen challenge in a mouse model of asthma. Int Arch Allergy Immunol. 2012; 158: 252-260. Ref.: https://goo.gl/q8F5EQ
  8. Zincke T. Mittheilungen aus dem chemischen Laboratorium der Universitat Marburg. Justus Leibigs Annals Chemie. 1905; 343: 75-99.
  9. Dodds Ec, Huang Rl, Lawson W, Robinson R. Synthetic oestrogenic compounds related to stilbene and diphenylethane. III. Proc R Soc Lond B Biol Sci. 1953; 140: 470-497. Ref.: https://goo.gl/bwPkuJ
  10. Akinbami LJ, Moorman JE, Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009. Natl Health Stat Report. 2011; 1-14. Ref.: https://goo.gl/Vb5s66
  11. Tilson HA. Collection Bisohenol A (BPA). Env Health Perspectives. 2012; 1-37.
  12. Hines EP, Mendola P, von Ehrenstein OS, Ye X, Calafat AM, et al. Concentrations of environmental phenols and parabens in milk, urine and serum of lactating North Carolina women. Reprod Toxicol. 2015; 54: 120-128. Ref.: https://goo.gl/ahcDqZ
  13. Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007; 24: 139-177. Ref.: https://goo.gl/oZQTtA
  14. Lv Y, Lu S, Dai Y, Rui C, Wang Y, et al. Higher dermal exposure of cashiers to BPA and its association with DNA oxidative damage. Environ Int. 2017; 98: 69-74. Ref.: https://goo.gl/FfKhXY
  15. Hormann AM, Vom Saal FS, Nagel SC, Stahlhut RW, Moyer CL, et al. Holding thermal receipt paper and eating food after using hand sanitizer results in high serum bioactive and urine total levels of bisphenol A (BPA). PLoS One. 2014; 9: e110509. Ref.: https://goo.gl/DCiDgm
  16. Nakajima Y, Goldblum RM, Midoro-Horiuti T. Fetal exposure to bisphenol A as a risk factor for the development of childhood asthma: an animal model study. Environ Health. 2012; 11: 1-7. Ref.: https://goo.gl/Th2j3o
  17. Vinas R, Goldblum RM, Watson CS. Rapid estrogenic signaling activities of the modified (chlorinated, sulfonated, and glucuronidated) endocrine disruptor bisphenol A. Endocrine Disruptors. 2013; 1: e25411. Ref.: https://goo.gl/BWoQJ5
  18. Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJ, et al. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect. 2010; 118: 1055-1070. Ref.: https://goo.gl/UDJAQk
  19. Vaidya SV, Kulkarni H. Association of Urinary Bisphenol A Concentration with Allergic Asthma: Results from the National Health and Nutrition Examination Survey 2005-2006. J Asthma. 2012; 49: 800-806. Ref.: https://goo.gl/4D6xWP
  20. Spanier AJ, Kahn RS, Kunselman AR, Hornung R, Xu Y, et al. Prenatal exposure to bisphenol a and child wheeze from birth to 3 years of age. Environ Health Perspect. 2012; 120: 916-920. Ref.: https://goo.gl/fCj5PZ
  21. Spanier AJ, Kahn RS, Kunselman AR, Schaefer EW, Hornung R, et al. Bisphenol A Exposure and the Development of Wheeze and Lung Function in Children Through Age 5 Years. JAMA Pediatr. 2014; 168: 1131-1137. Ref.: https://goo.gl/HkVeRi
  22. Donohue KM, Miller RL, Perzanowski MS, Just AC, Hoepner LA, et al. Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children. J Allergy Clin Immunol. 2013; 131: 726-742. Ref.: https://goo.gl/rcN1Pc
  23. Kim K, Kim J, Kwon H, Hong S, Kim B, et al. Bisphenol A Exposure and Asthma Development in School-Age Children: A Longitudinal Study. PLOS One. 2014b; 9: e111383. Ref.: https://goo.gl/ab8Tus
  24. Whyatt RM, Rundle AG, Perzanowski MS, Just AC, Donohue KM, et al. Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children. J Allergy Clin Immunol. 2014; 134: 1195-1197. Ref.: https://goo.gl/YJtU2y
  25. Gascon M, Casas M, Morales E, Valvi D, Ballesteros-Gomez A, et al. Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy. J Allergy Clin Immunol. 2015; 135: 370-378. Ref.: https://goo.gl/NYK335
  26. Wang IJ, Chen CY, Bornehag CG. Bisphenol A exposure may increase the risk of development of atopic disorders in children. Int J Hyg Environ Health. 2016; 219: 311-316. Ref.: https://goo.gl/vm1CEs
  27. Kim JH, Sartor MA, Rozek LS, Faulk C, Anderson OS, et al. Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome. BMC Genomics. 2014a; 15: 30. Ref.: https://goo.gl/G4fCRz
  28. Larsson K, Ljung BK, Palm B, Wennberg M, Kaj L, et al. Exposure determinants of phthalates, parabens, bisphenol A and triclosan in Swedish mothers and their children. Environ Int. 2014; 73: 323-333. Ref.: https://goo.gl/Tm5smM
  29. Covaci A, Hond ED, Geens T, Govarts E, Koppen G, et al. Urinary BPA measurements in children and mothers from six European member states: Overall results and determinants of exposure. Environ Res. 2015; 141: 77-85. Ref.: https://goo.gl/999Gex
  30. Midoro-Horiuti T, Tiwari R, Watson CS, Goldblum RM. Maternal exposure to bisphenol A enhances susceptibility to experimental allergic asthma in their pups. Env Health Perspectives. 2010; 118: 273-277.
  31. Bauer SM, Roy A, Emo J, Chapman TJ, Georas SN, et al. The effects of maternal exposure to bisphenol A on allergic lung inflammation into adulthood. Toxicol Sci. 2012; 130: 82-93. Ref.: https://goo.gl/rHdZxY
  32. Petzold S, Averbeck M, Simon JC, Lehmann I, Polte T. Lifetime-dependent effects of bisphenol A on asthma development in an experimental mouse model. PLoS One. 2014; 9: e100468. Ref.: https://goo.gl/7h8PLJ
  33. O'Brien E, Bergin IL, Dolinoy DC, Zaslona Z, Little RJ, et al. Perinatal bisphenol A exposure beginning before gestation enhances allergen sensitization, but not pulmonary inflammation, in adult mice. J Dev Orig Health Dis. 2014; 5: 121-131. Ref.: https://goo.gl/Qcr4zF
  34. Nygaard UC, Vinje NE, Samuelsen M, Andreassen M, Groeng EC, et al. Early life exposure to bisphenol A investigated in mouse models of airway allergy, food allergy and oral tolerance. Food Chem Toxicol. 2015; 83: 17-25. Ref.: https://goo.gl/E65agS
  35. Leme AS, Hubeau C, Xiang Y, Goldman A, Hamada K, et al. Role of breast milk in a mouse model of maternal transmission of asthma susceptibility. J Immunol. 2006; 176: 762-769. Ref.: https://goo.gl/4FnZaH
  36. Midoro-Horiuti T. Environmental estrogens and allergy. Japanese Journal of Pediatric Intaractable Asthma and Allergic Diseases. 2014; 12: 311-314.
  37. Bronson FH, Dagg CP, Snell GD. Reproduction. In: Green,E.L. (Ed.), Biology of the Laboratory Mouse. Dover Publications, INC. New York. 2007.
  38. Bachmanov AA, Reed DR, Beauchamp GK, Tordoff MG. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet. 2002; 32: 435-443. Ref.: https://goo.gl/SQPtVE
  39. Allam JP, Zivanovic O, Berg C, Gembruch U, Bieber T, et al. In search for predictive factors for atopy in human cord blood. Allergy. 2005; 60: 743-750. Ref.: https://goo.gl/Jcsbez
  40. Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol. 1998; 160: 4730-4737. Ref.: https://goo.gl/dV5Mpu
  41. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, et al. Development of allergen-specific T-cell memory in atopic and normal children. Lancet. 1999; 353: 196-200. Ref.: https://goo.gl/Q6s9MX
  42. Gern JE, Lemanske RF Jr, Busse WW. Early life origins of asthma. J Clin Invest. 1999; 104: 837-843. Ref.: https://goo.gl/gvTu2v
  43. Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy. 2000; 55: 688-697. Ref.: https://goo.gl/unJVx8
  44. Strakovsky RS, Wang H, Engeseth NJ, Flaws JA, Helferich WG, 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. Ref.: https://goo.gl/wiZny4
  45. Maccani MA, Marsit CJ. Exposure and fetal growth-associated miRNA alterations in the human placenta. Clin Epigenetics. 2011; 2: 401-404. Ref.: https://goo.gl/LiR6SY
  46. Dhimolea E, Wadia PR, Murray TJ, Settles ML, Treitman JD, et al. Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development. PLoS One. 2014; 9: e99800. Ref.: https://goo.gl/wM6NP9
  47. Li G, Chang H, Xia W, Mao Z, Li Y, et al. F0 maternal BPA exposure induced glucose intolerance of F2 generation through DNA methylation change in Gck. Toxicol Lett. 2014; 228: 192-199. Ref.: https://goo.gl/Fj28CP
  48. Bastos SL, Kamstra JH, Cenijn PH, van Rijt LS, Hamers T, et al. Effects of endocrine disrupting chemicals on In Vitro global DNA methylation and adipocyte differentiation. Toxicol In Vitro. 2013; 27: 1634-1643. Ref.: https://goo.gl/5H6LWe
  49. Warita K, Mitsuhashi T, Ohta K, Suzuki S, Hoshi N, et al. Gene expression of epigenetic regulatory factors related to primary silencing mechanism is less susceptible to lower doses of bisphenol A in embryonic hypothalamic cells. J Toxicol Sci. 2013; 38: 285-289. Ref.: https://goo.gl/sCo2Hj
  50. 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. Ref.: https://goo.gl/DSbpEx
  51. Doshi T, Mehta SS, Dighe V, Balasinor N, Vanage G. Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. Toxicology. 2011; 289: 74-82. Ref.: https://goo.gl/8AFvsp
  52. Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS. Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J. 2010; 24: 2273-2280. Ref.: https://goo.gl/kiUQgb
  53. Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer. 2010; 1: 146-155. Ref.: https://goo.gl/ak8jsj
  54. Trapphoff T, Heiligentag M, El Hajj N, Haaf T, Eichenlaub-Ritter U. Chronic exposure to a low concentration of bisphenol A during follicle culture affects the epigenetic status of germinal vesicles and metaphase II oocytes. Fertil Steril. 2013; 100: 1758-1767. Ref.: https://goo.gl/4HikbX
  55. Doshi T, D'souza C, Dighe V, Vanage G. Effect of neonatal exposure on male rats to bisphenol A on the expression of DNA methylation machinery in the postimplantation embryo. J Biochem Mol Toxicol. 2012; 26: 337-343. Ref.: https://goo.gl/wWeH99
  56. Avissar-Whiting M, Veiga KR, Uhl KM, Maccani MA, Gagne LA, et al. Bisphenol A exposure leads to specific microRNA alterations in placental cells. Reprod Toxicol. 2010; 29: 401-406. Ref.: https://goo.gl/AyHLzH
  57. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA. 2007; 104: 13056-13061. Ref.: https://goo.gl/Sejh9t
  58. Yeo M, Berglund K, Hanna M, Guo JU, Kittur J, et al. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci USA. 2013; 110: 4315-4320. Ref.: https://goo.gl/TmygRn
  59. Yaoi T, Itoh K, Nakamura K, Ogi H, Fujiwara Y, et al. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem Biophys Res Commun. 2008; 376: 563-567. Ref.: https://goo.gl/3BLehT
  60. Patella V, Giuliano A, Bouvet JP, Marone G. Endogenous superallergen protein Fv induces IL-4 secretion from human Fc epsilon RI+ cells through interaction with the VH3 region of IgE. J Immunol. 1998; 161: 5647-5655. Ref.: https://goo.gl/DxR4TP
  61. Kim JH, Rozek LS, Soliman AS, Sartor MA, Hablas A, et al. Bisphenol A-associated epigenomic changes in prepubescent girls: a cross-sectional study in Gharbiah, Egypt. Environ Health. 2013; 12: 12-33. Ref.: https://goo.gl/UBMptm
  62. Wong RL, Walker CL. Molecular pathways: environmental estrogens activate nongenomic signaling to developmentally reprogram the epigenome. Clin Cancer Res. 2013; 19: 3732-3737. Ref.: https://goo.gl/R7FR59
  63. Jeng YJ, Watson CS. Combinations of physiologic estrogens with xenoestrogens alter ERK phosphorylation profiles in rat pituitary cells. Environ Health Perspect. 2011; 119: 104-112. Ref.: https://goo.gl/boz1T3
  64. Chang LC, Lin HY, Tsai MT, Chou RH, Lee FY, et al. YC-1 inhibits proliferation of breast cancer cells by down regulating EZH2 expression via activation of c-Cbl and ERK. Br J Pharmacol. 2014; 171: 4010-4025. Ref.: https://goo.gl/gVLMmS
  65. Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002; 111: 197-208. Ref.: https://goo.gl/iT9CyF
  66. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002; 16: 2893-2905. Ref.: https://goo.gl/jS6fmB
  67. Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002; 111: 185-196. Ref.: https://goo.gl/mLmecg
  68. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002; 298: 1039-1043. Ref.: https://goo.gl/BuhaKb
  69. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, et al. Estrogen Receptor {alpha} (ER{alpha}) Deficiency in Macrophages Results in Increased Stimulation of CD4+ T Cells while 17{beta}-Estradiol Acts through ER{alpha} to Increase IL-4 and GATA-3 Expression in CD4+ T Cells Independent of Antigen Presentation. J Immunol. 2005; 175: 5716-5723. Ref.: https://goo.gl/nkpqej
  70. Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, et al. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol Immunol. 2007; 44: 1987-1995. Ref.: https://goo.gl/s2idwm
  71. He S, Xie F, Liu Y, Tong Q, Mochizuki K, et al. The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. Blood. 2013; 122: 4119-4128. Ref.: https://goo.gl/4yG6zo
  72. Jacob E, Hod-Dvorai R, Schif-Zuck S, Avni O. Unconventional association of the polycomb group proteins with cytokine genes in differentiated T helper cells. J Biol Chem. 2008; 283: 13471-13481. Ref.: https://goo.gl/QDd14d
  73. Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, et al. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity. 2013; 39: 819-832. Ref.: https://goo.gl/EpeHw1
  74. Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, et al. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem. 2005; 280: 31470-31477. Ref.: https://goo.gl/HjZGog
  75. Bredfeldt TG, Greathouse KL, Safe SH, Hung MC, Bedford MT, et al. Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol. 2010; 24: 993-1006. Ref.: https://goo.gl/2KbVSw
  76. Greathouse KL, Bredfeldt T, Everitt JI, Lin K, Berry T, et al. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res. 2012; 10: 546-557. Ref.: https://goo.gl/ztTtxa
  77. Shimizu M, Ohta K, Matsumoto Y, Fukuoka M, Ohno Y, et al. Sulfation of bisphenol A abolished its estrogenicity based on proliferation and gene expression in human breast cancer MCF7 cells. Toxicol In Vitro. 2002; 16: 549-556. Ref.: https://goo.gl/tPxh8V
  78. Fedulov AV, Kobzik L. Allergy risk is mediated by dendritic cells with congenital epigenetic changes. Am J Respir Cell Mol Biol. 2011; 44: 285-292. Ref.: https://goo.gl/kUEGHz
  79. Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008; 118: 3462-3469. Ref.: https://goo.gl/438pQB
  80. Liu J, Ballaney M, Al-alem U, Quan C, Jin X, et al. Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo. Toxicol Sci. 2008; 102: 76-81. Ref.: https://goo.gl/pCAKzp


Figure 1

Figure 1

Figure 1

Figure 2

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More