CoChat
Sign Up
Cited by 61Effects and risks of endocrine disrupting chemicalsEpigenetics and DNA MethylationBirth, Development, and Health

Prenatal bisphenol A exposure is linked to epigenetic changes in glutamate receptor subunit gene Grin2b in female rats and humans

Open access
Alavian-Ghavanini, Ali, Lin, Ping-I, Lind, P. Monica, Risén Rimfors, Sabina, Halin Lejonklou, Margareta, Dunder, Linda, Tang, Mandy, Lindh, Christian +2 more·2018·Scientific Reports
DOI 10.1038/s41598-018-29732-9PMC PMC6063959
Open this paper in CoChat — free accountOpen PDF

Abstract

Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, low APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and low APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-018-29732-9

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 63

  1. [1]Mikolajewska K Stragierowicz J Gromadzinska J Bisphenol A - Application, sources of exposure and potential risks in infants, children and pregnant women International journal of occupational medicine and environmental health 2015 28 209 241 26182919
  2. [4]WHO/UNEP. State of the science of endocrine disrupting chemicals (2013). 24530840
  3. [5]Diamanti-Kandarakis E Endocrine-disrupting chemicals: an Endocrine Society scientific statement Endocr Rev 2009 30 293 342 10.1210/er.2009-0002 19502515 PMC2726844 · DOI · Paper page
  4. [6]Gore AC EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals Endocr Rev 2015 36 E1 E150 10.1210/er.2015-1010 26544531 PMC4702494 · DOI · Paper page
  5. [7]Varshney, M. & Nalvarte, I. Genes, Gender, Environment, and Novel Functions of Estrogen Receptor Beta in the Susceptibility to Neurodevelopmental Disorders. Brain sciences7, 10.3390/brainsci7030024 (2017). PMC5366823 28241485 · DOI
  6. [8]Berenbaum SA Beltz AM Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones Frontiers in neuroendocrinology 2011 32 183 200 10.1016/j.yfrne.2011.03.001 21397624 · DOI
  7. [10]Mustieles V Perez-Lobato R Olea N Fernandez MF Bisphenol A: Human exposure and neurobehavior Neurotoxicology 2015 49 174 184 10.1016/j.neuro.2015.06.002 26121921 · DOI
  8. [11]Ejaredar, M., Lee, Y., Roberts, D. J., Sauve, R. & Dewey, D. Bisphenol A exposure and children’s behavior: A systematic review. Journal of exposure science & environmental epidemiology, 10.1038/jes.2016.8 (2016). 26956939 · DOI
  9. [12]Negri-Cesi, P. Bisphenol A Interaction With Brain Development and Functions. Dose Response13, 10.1177/1559325815590394 (2015). PMC4674177 26672480 · DOI
  10. [13]McCabe C Anderson OS Montrose L Neier K Dolinoy DC Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism Current environmental health reports 2017 4 426 438 10.1007/s40572-017-0170-z 28980159 PMC5784425 · DOI
  11. [14]Kundakovic M Champagne FA Epigenetic perspective on the developmental effects of bisphenol A Brain, behavior, and immunity 2011 25 1084 1093 10.1016/j.bbi.2011.02.005 21333735 PMC3703316 · DOI
  12. [15]Mileva G Baker SL Konkle AT Bielajew C Bisphenol-A: epigenetic reprogramming and effects on reproduction and behavior International journal of environmental research and public health 2014 11 7537 7561 10.3390/ijerph110707537 25054232 PMC4113893 · DOI
  13. [16]Jacobs MN Marczylo EL Guerrero-Bosagna C Rüegg J Marked for Life: Epigenetic Effects of Endocrine Disrupting Chemicals Annu. Rev. Environ. Resour. 2017 42 105 160 10.1146/annurev-environ-102016-061111 · DOI
  14. [17]Bale TL Epigenetic and transgenerational reprogramming of brain development Nat Rev Neurosci 2015 16 332 344 10.1038/nrn3818 25921815 PMC7064155 · DOI · Paper page
  15. [18]Keverne EB Significance of epigenetics for understanding brain development, brain evolution and behaviour Neuroscience 2014 264 207 217 10.1016/j.neuroscience.2012.11.030 23201253 · DOI
  16. [19]Marczylo EL Jacobs MN Gant TW Environmentally induced epigenetic toxicity: potential public health concerns Critical reviews in toxicology 2016 46 676 700 10.1080/10408444.2016.1175417 27278298 PMC5030620 · DOI
  17. [21]Kitraki E Nalvarte I Alavian-Ghavanini A Ruegg J Developmental exposure to bisphenol A alters expression and DNA methylation of Fkbp5, an important regulator of the stress response Mol Cell Endocrinol 2015 417 191 199 10.1016/j.mce.2015.09.028 26427651 · DOI
  18. [22]Kundakovic M DNA methylation of BDNF as a biomarker of early-life adversity Proceedings of the National Academy of Sciences of the United States of America 2015 112 6807 6813 10.1073/pnas.1408355111 25385582 PMC4460453 · DOI · Paper page
  19. [23]Dorval KM Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder Genes Brain Behav 2007 6 444 452 10.1111/j.1601-183X.2006.00273.x 17010153 PMC4833492 · DOI
  20. [24]Hu C Chen W Myers SJ Yuan H Traynelis SF Human GRIN2B variants in neurodevelopmental disorders J Pharmacol Sci 2016 132 115 121 10.1016/j.jphs.2016.10.002 27818011 PMC5125235 · DOI
  21. [25]Martucci L N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels Schizophr Res 2006 84 214 221 10.1016/j.schres.2006.02.001 16549338 · DOI
  22. [26]Cull-Candy S Brickley S Farrant M NMDA receptor subunits: diversity, development and disease Curr Opin Neurobiol 2001 11 327 335 10.1016/S0959-4388(00)00215-4 11399431 · DOI · Paper page
  23. [27]Priya A Johar K Wong-Riley MT Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission Biochim Biophys Acta 2013 1833 48 58 10.1016/j.bbamcr.2012.10.014 23085505 PMC3518722 · DOI
  24. [29]Marsman A Glutamate in schizophrenia: a focused review and meta-analysis of (1)H-MRS studies Schizophr Bull 2013 39 120 129 10.1093/schbul/sbr069 21746807 PMC3523901 · DOI · Paper page
  25. [30]van Elst LT Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study Biol Psychiatry 2005 58 724 730 10.1016/j.biopsych.2005.04.041 16018980 · DOI
  26. [31]Kunz N Developmental and metabolic brain alterations in rats exposed to bisphenol A during gestation and lactation Int J Dev Neurosci 2011 29 37 43 10.1016/j.ijdevneu.2010.09.009 20955774 · DOI
  27. [32]Monyer H Burnashev N Laurie DJ Sakmann B Seeburg PH Developmental and regional expression in the rat brain and functional properties of four NMDA receptors Neuron 1994 12 529 540 10.1016/0896-6273(94)90210-0 7512349 · DOI · Paper page
  28. [33]Alonso-Magdalena P Rivera FJ Guerrero-Bosagna C Bisphenol-A and metabolic diseases: epigenetic, developmental and transgenerational basis Environ Epigenet 2016 2 dvw022 10.1093/eep/dvw022 29492299 PMC5804535 · DOI
  29. [34]Bornehag CG The SELMA study: a birth cohort study in Sweden following more than 2000 mother-child pairs Paediatr Perinat Epidemiol 2012 26 456 467 10.1111/j.1365-3016.2012.01314.x 22882790 · DOI
  30. [35]Choi YS Kim S Kyu Lee H Lee KU Pak YK In vitro methylation of nuclear respiratory factor-1 binding site suppresses the promoter activity of mitochondrial transcription factor A Biochem Biophys Res Commun 2004 314 118 122 10.1016/j.bbrc.2003.12.065 14715254 · DOI
  31. [36]Wang J NRF1 coordinates with DNA methylation to regulate spermatogenesis FASEB J 2017 31 4959 4970 10.1096/fj.201700093R 28754714 PMC5636708 · DOI
  32. [37]Karolchik D The UCSC Genome Browser database: 2014 update Nucleic acids research 2014 42 D764 770 10.1093/nar/gkt1168 24270787 PMC3964947 · DOI · Paper page
  33. [38]Faulk C Detection of differential DNA methylation in repetitive DNA of mice and humans perinatally exposed to bisphenol A Epigenetics 2016 11 489 500 10.1080/15592294.2016.1183856 27267941 PMC4939917 · DOI
  34. [39]Jantzie LL Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain Cereb Cortex 2015 25 482 495 10.1093/cercor/bht246 24046081 PMC4303802 · DOI
  35. [40]Shu, H. et al. Temporal Trends of Phthalate Exposures during 2007–2010 in Swedish Pregnant Women (2017). 29472621
  36. [44]Langie SA Whole-Genome Saliva and Blood DNA Methylation Profiling in Individuals with a Respiratory Allergy PLoS One 2016 11 e0151109 10.1371/journal.pone.0151109 26999364 PMC4801358 · DOI
  37. [45]Slieker RC Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array Epigenetics & chromatin 2013 6 26 10.1186/1756-8935-6-26 23919675 PMC3750594 · DOI
  38. [48]Robinson CM Neary R Levendale A Watson CJ Baugh JA Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype Respir Res 2012 13 74 10.1186/1465-9921-13-74 22938014 PMC3519562 · DOI
  39. [49]Xu X Hypoxia-induced endothelial-mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells FEBS Lett 2016 590 1222 1233 10.1002/1873-3468.12158 27012941 · DOI
  40. [50]Yuen RK Chen B Blair JD Robinson WP Nelson DM Hypoxia alters the epigenetic profile in cultured human placental trophoblasts Epigenetics 2013 8 192 202 10.4161/epi.23400 23314690 PMC3592905 · DOI
  41. [51]Almgren M Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? American journal of obstetrics and gynecology 2014 211 502 e501 508 10.1016/j.ajog.2014.05.014 24996659 · DOI
  42. [52]Ehrenstein V Association of Apgar score at five minutes with long-term neurologic disability and cognitive function in a prevalence study of Danish conscripts BMC Pregnancy Childbirth 2009 9 14 10.1186/1471-2393-9-14 19341459 PMC2670812 · DOI
  43. [53]Li J Olsen J Vestergaard M Obel C Low Apgar scores and risk of childhood attention deficit hyperactivity disorder J Pediatr 2011 158 775 779 10.1016/j.jpeds.2010.10.041 21238979 · DOI
  44. [54]Polo-Kantola P Obstetric risk factors and autism spectrum disorders in Finland J Pediatr 2014 164 358 365 10.1016/j.jpeds.2013.09.044 24183209 · DOI
  45. [55]Zhou R Chen F Chang F Bai Y Chen L Persistent overexpression of DNA methyltransferase 1 attenuating GABAergic inhibition in basolateral amygdala accounts for anxiety in rat offspring exposed perinatally to low-dose bisphenol A Journal of psychiatric research 2013 47 1535 1544 10.1016/j.jpsychires.2013.05.013 23791455 · DOI · Paper page
  46. [56]Kurian JR The Methylcytosine Dioxygenase Ten-Eleven Translocase-2 (tet2) Enables Elevated GnRH Gene Expression and Maintenance of Male Reproductive Function Endocrinology 2016 157 3588 3603 10.1210/en.2016-1087 27384303 PMC5007894 · DOI
  47. [57]Liu Y Oestrogen receptor beta regulates epigenetic patterns at specific genomic loci through interaction with thymine DNA glycosylase Epigenetics & chromatin 2016 9 7 10.1186/s13072-016-0055-7 26889208 PMC4756533 · DOI
  48. [58]Lejonklou MH Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring Environ Health Perspect 2017 125 067018 10.1289/EHP505 28657538 PMC5743697 · DOI
  49. [59]Lind T Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring Environ Res 2017 159 61 68 10.1016/j.envres.2017.07.020 28772150 · DOI
  50. [61]Vandenberg LN Hauser R Marcus M Olea N Welshons WV Human exposure to bisphenol A (BPA) Reprod Toxicol 2007 24 139 177 10.1016/j.reprotox.2007.07.010 17825522 · DOI
  51. [62]Churchwell MI Comparison of life-stage-dependent internal dosimetry for bisphenol A, ethinyl estradiol, a reference estrogen, and endogenous estradiol to test an estrogenic mode of action in Sprague Dawley rats Toxicol Sci 2014 139 4 20 10.1093/toxsci/kfu021 24496641 PMC4038784 · DOI
  52. [63]Calafat AM Misuse of blood serum to assess exposure to bisphenol A and phthalates Breast Cancer Res 2013 15 403 10.1186/bcr3494 24083327 PMC3978629 · DOI
  53. [64]Bornehag CG Prenatal phthalate exposures and anogenital distance in Swedish boys Environmental health perspectives 2015 123 101 107 25353625 PMC4286276
  54. [65]Berge, T. L., Lygre, G. B., Jonsson, B. A., Lindh, C. H. & Bjorkman, L. Bisphenol A concentration in human saliva related to dental polymer-based fillings. Clin Oral Investig, 10.1007/s00784-017-2055-9 (2017). 28181074 · DOI
  55. [66]Mazzachi BC Peake MJ Ehrhardt V Reference range and method comparison studies for enzymatic and Jaffe creatinine assays in plasma and serum and early morning urine Clinical laboratory 2000 46 53 55 10745982
  56. [67]Lindh CH Blood serum concentrations of perfluorinated compounds in men from Greenlandic Inuit and European populations Chemosphere 2012 88 1269 1275 10.1016/j.chemosphere.2012.03.049 22494529 · DOI
  57. [68]Jefferis BJ Cotinine-assessed second-hand smoke exposure and risk of cardiovascular disease in older adults Heart 2010 96 854 10.1136/hrt.2009.191148 20478864 PMC2921288 · DOI
  58. [69]Liu L Decomposition of RNA methylome reveals co-methylation patterns induced by latent enzymatic regulators of the epitranscriptome Mol Biosyst 2015 11 262 274 10.1039/C4MB00604F 25370990 PMC4253022 · DOI
  59. [70]Tsuji S Network-based analysis for identification of candidate genes for colorectal cancer progression Biochem Biophys Res Commun 2016 476 534 540 10.1016/j.bbrc.2016.05.158 27255996 · DOI
  60. [71]Lord E Diallo AB Makarenkov V Classification of bioinformatics workflows using weighted versions of partitioning and hierarchical clustering algorithms BMC Bioinformatics 2015 16 68 10.1186/s12859-015-0508-1 25887434 PMC4354763 · DOI
  61. [72]Montalvo-Ortiz JL The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect Behav Brain Res 2016 315 71 74 10.1016/j.bbr.2016.08.010 27506655 PMC5396458 · DOI
  62. [73]Satta R Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons Proceedings of the National Academy of Sciences of the United States of America 2008 105 16356 16361 10.1073/pnas.0808699105 18852456 PMC2570996 · DOI
  63. [74]Khan A JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework Nucleic Acids Res 2018 46 D260 D266 10.1093/nar/gkx1126 29140473 PMC5753243 · DOI

Cited by

Sorted by citations

Authors
Alavian-Ghavanini, A., Lin, P.-I., Lind, P. M., Risén Rimfors, S., Halin Lejonklou, M., Dunder, L., Tang, M., Lindh, C., Bornehag, C.-G., & Rüegg, J.
Affiliations
  • Karlstad University (SE)
  • Uppsala University (SE)
  • Karolinska Institutet (SE)
  • Lund University (SE)
Corresponding author
Rüegg, Joëlle
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-07-27
Volume
8
Issue
1
Pages
11315-11315
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-29732-9
PMC
PMC6063959
OpenAlex
W2883852411
Cited by
61
References
8
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 12 · 2021: 11 · 2020: 7 · 2019: 6
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Diva portal (Dalarna University Library) (submittedVersion, other-oa)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Svenska Forskningsrådet Formas (216-2013-1966, 216-2012-475)
  • EC | Horizon 2020 (634880)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
bisphenol A, prenatal exposure, NR2B subunit, DNA methylation, epigenetic regulation, glutamate receptors, sex differences, brain development, Apgar score, children, rats, neurodevelopmental disorders
MeSH terms
Bisphenol A Compounds, Animals, Benzhydryl Compounds, Child, Female, Gene Expression Regulation, Humans, Male, Phenols, Pregnancy, Prenatal Exposure Delayed Effects, Sex Characteristics, Receptors, N-Methyl-D-Aspartate, DNA Methylation, Epigenesis, Genetic, Mice, Rats, Endocrine Disruptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review