https://doi.org/10.4081/ejh.2021.3272
Effects of chronic exposure to bisphenol A in adult female mice on social behavior, vasopressin system, and estrogen membrane receptor (GPER1)
Submitted: 7 May 2021
Accepted: 20 October 2021
Published: 10 November 2021
Accepted: 20 October 2021
Abstract Views: 1149
PDF: 581
HTML: 28
HTML: 28
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Bisphenol A (BPA), an organic synthetic compound found in some plastics and epoxy resins, is classified as an endocrine disrupting chemical. Exposure to BPA is especially dangerous if it occurs during specific “critical periods” of life, when organisms are more sensitive to hormonal changes (i.e., intrauterine, perinatal, juvenile or puberty periods). In this study, we focused on the effects of chronic exposure to BPA in adult female mice starting during pregnancy. Three months old C57BL/6J females were orally exposed to BPA or to vehicle (corn oil). The treatment (4 µg/kg body weight/day) started the day 0 of pregnancy and continued throughout pregnancy, lactation, and lasted for a total of 20 weeks. BPA-treated dams did not show differences in body weight or food intake, but they showed an altered estrous cycle compared to the controls. In order to evidence alterations in social and sociosexual behaviors, we performed the Three-Chamber test for sociability, and analyzed two hypothalamic circuits (well-known targets of endocrine disruption) particularly involved in the control of social behavior: the vasopressin and the oxytocin systems. The test revealed some alterations in the displaying of social behavior: BPA-treated dams have higher locomotor activity compared to the control dams, probably a signal of high level of anxiety. In addition, BPA-treated dams spent more time interacting with no-tester females than with no-tester males. In brain sections, we observed a decrease of vasopressin immunoreactivity (only in the paraventricular and suprachiasmatic nuclei) of BPA-treated females, while we did not find any alteration of the oxytocin system. In parallel, we have also observed, in the same hypothalamic nuclei, a significant reduction of the membrane estrogen receptor GPER1 expression.
Frye CA, Bo E, Calamandrei G, Calza L, Dessi-Fulgheri F, Fernandez M, et al. Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. J Neuroendocrinol 2012;24:144-59.
DOI: https://doi.org/10.1111/j.1365-2826.2011.02229.x
Catenza CJ, Farooq A, Shubear NS, Donkor KK. A targeted review on fate, occurrence, risk and health implications of bisphenol analogues. Chemosphere 2021;268:129273.
DOI: https://doi.org/10.1016/j.chemosphere.2020.129273
Lehmler HJ, Liu B, Gadogbe M, Bao W. Exposure to bisphenol A, bisphenol F, and bisphenol S in U.S. adults and children: The national health and nutrition examination survey 2013-2014. ACS Omega 2018;3:6523-32.
DOI: https://doi.org/10.1021/acsomega.8b00824
Bonaldo B, Marraudino M, Casile A, Bettarelli M, Gotti S, Panzica GC. Effects of chronic exposure to Bisphenol-A in pregnant female mice. In: Proceedings 30th National Conference of the Italian Group for the Study of Neuromorphology, Turin, 2020. Eur J Histochem 2020;64:3200.
MacKay H, Abizaid A. A plurality of molecular targets: The receptor ecosystem for bisphenol-A (BPA). Horm Behav 2018;101:59-67.
DOI: https://doi.org/10.1016/j.yhbeh.2017.11.001
Murata M, Kang JH. Bisphenol A (BPA) and cell signaling pathways. Biotechnol Adv 2018;36:311-27.
DOI: https://doi.org/10.1016/j.biotechadv.2017.12.002
Marraudino M, Bonaldo B, Farinetti A, Panzica G, Ponti G, Gotti S. Metabolism disrupting chemicals and alteration of neuroendocrine circuits controlling food intake and energy metabolism. Front Endocrinol (Lausanne) 2019;9:766.
DOI: https://doi.org/10.3389/fendo.2018.00766
Street ME, Angelini S, Bernasconi S, Burgio E, Cassio A, Catellani C, et al. Current knowledge on endocrine disrupting chemicals (EDCs) from animal biology to humans, from pregnancy to adulthood: Highlights from a National Italian Meeting. Int J Mol Sci 2018;19:1647.
DOI: https://doi.org/10.3390/ijms19061647
Abel JL, Rissman EF. Location, location, location: Genetic regulation of neural sex differences. Rev Endocr Metab Disord 2012;13:151-61.
DOI: https://doi.org/10.1007/s11154-011-9186-0
Bosch OJ, Neumann ID. Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: from central release to sites of action. Horm Behav 2012;61:293-303.
DOI: https://doi.org/10.1016/j.yhbeh.2011.11.002
Keller M, Vandenberg LN, Charlier TD. The parental brain and behavior: A target for endocrine disruption. Front Neuroendocrinol 2019;54:100765.
DOI: https://doi.org/10.1016/j.yfrne.2019.100765
Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012;35:649-59.
DOI: https://doi.org/10.1016/j.tins.2012.08.004
Caldwell HK. Oxytocin and vasopressin: Powerful regulators of social behavior. Neuroscientist 2017;23:517-28.
DOI: https://doi.org/10.1177/1073858417708284
Dumais KM, Veenema AH. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 2016;40:1-23.
DOI: https://doi.org/10.1016/j.yfrne.2015.04.003
Smith CJW, DiBenedictis BT, Veenema AH. Comparing vasopressin and oxytocin fiber and receptor density patterns in the social behavior neural network: Implications for cross-system signaling. Front Neuroendocrinol 2019;53:100737.
DOI: https://doi.org/10.1016/j.yfrne.2019.02.001
Panzica GC, Mura E, Pessatti M, Viglietti Panzica C. Early embryonic administration of xenoestrogens alters vasotocin system and male sexual behavior of the Japanese quail. Domest Anim Endocrin 2005;29:436-45.
DOI: https://doi.org/10.1016/j.domaniend.2005.02.010
Panzica GC, Viglietti-Panzica C, Mura E, Quinn Jr MJ, Palanza P, Ottinger MA. Effects of xenoestrogens on the differentiation of behaviorally relevant neural circuits. Front Neuroendocrinol 2007;28:179-200.
DOI: https://doi.org/10.1016/j.yfrne.2007.07.001
Gore AC, Krishnan K, Reilly MP. Endocrine-disrupting chemicals: Effects on neuroendocrine systems and the neurobiology of social behavior. Horm Behav 2019;111:7-22.
DOI: https://doi.org/10.1016/j.yhbeh.2018.11.006
Patisaul HB. Endocrine disruption of vasopressin systems and related behaviors. Front Endocrinol (Lausanne) 2017;8:134.
DOI: https://doi.org/10.3389/fendo.2017.00134
Marraudino M, Carrillo B, Bonaldo B, Llorente R, Campioli E, Garate I, et al. G Protein-coupled estrogen receptor immunoreactivity in the rat hypothalamus is widely distributed in neurons, astrocytes, and oligodendrocytes, fluctuates during the estrous cycle, and is sexually dimorphic. Neuroendocrinology 2021;111:660-77.
DOI: https://doi.org/10.1159/000509583
Palanza PL, Howdeshell KL, Parmigiani S, vom Saal FS. Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice. Environ Health Perspect 2002;110:415-22.
DOI: https://doi.org/10.1289/ehp.02110s3415
Bo E, Farinetti A, Marraudino M, Sterchele D, Eva C, Gotti S, et al. Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice. Andrology 2016;4:723-34.
DOI: https://doi.org/10.1111/andr.12222
McLean AC, Valenzuela N, Fai S, Bennett SAL. Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp 2012;67:e4389.
DOI: https://doi.org/10.3791/4389
Chang YC, Cole TB, Costa LG. Behavioral phenotyping for autism spectrum disorders in mice. Curr Protoc Toxicol 2017;72:11.22.1-11.22.21.
DOI: https://doi.org/10.1002/cptx.19
Marraudino M, Miceli D, Farinetti A, Ponti G, Panzica G, Gotti S. Kisspeptin innervation of the hypothalamic paraventricular nucleus: sexual dimorphism and effect of estrous cycle in female mice. J Anat 2017;230:775-86.
DOI: https://doi.org/10.1111/joa.12603
Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic Press; 2001.
Watson RE Jr., Wiegand SJ, Clough RW, Hoffman GE. Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology. Peptides 1986;7:155-9.
DOI: https://doi.org/10.1016/0196-9781(86)90076-8
Ponti G, Rodriguez-Gomez A, Farinetti A, Marraudino M, Filice F, Foglio B, et al. Early postnatal genistein administration permanently affects nitrergic and vasopressinergic systems in a sex-specific way. Neuroscience 2017;346:203-15.
DOI: https://doi.org/10.1016/j.neuroscience.2017.01.024
Sofroniew MV, Madler M, Müller OA, Scriba PC. A method for the consistent production of high quality antisera to small peptide hormones. Z Anal Chem 1978;290:163.
DOI: https://doi.org/10.1007/BF00482319
Sofroniew MV, Weindl A. Projections from the parvocellular vasopressin- and neurophysin-containing neurons of the suprachiasmatic nucleus. Am J Anat 1978;153:391-429.
DOI: https://doi.org/10.1002/aja.1001530305
Bean JC, Lin TW, Sathyamurthy A, Liu F, Yin DM, Xiong WC, et al. Genetic labeling reveals novel cellular targets of schizophrenia susceptibility gene: distribution of GABA and non-GABA ErbB4-positive cells in adult mouse brain. J Neurosci 2014;34:13549-66.
DOI: https://doi.org/10.1523/JNEUROSCI.2021-14.2014
Villanueva C, Jacquier S, de Roux N. DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons. PLoS One 2012;7:e36134.
DOI: https://doi.org/10.1371/journal.pone.0036134
Grassi D, Lagunas N, Pinos H, Panzica G, Garcia-Segura LM, Collado P. NADPH-diaphorase colocalizes with GPER and is modulated by the GPER agonist G1 in the SON and PVN of ovariectomized female rats. Neuroendocrinology 2017;104:94-104.
DOI: https://doi.org/10.1159/000445190
Hayward JN, Pavasuthipaisit K, Perez-Lopez FR, Sofroniew MV. Radioimmunoassay of arginine vasopressin in Rhesus monkey plasma. Endocrinology 1976;98:975-81.
DOI: https://doi.org/10.1210/endo-98-4-975
Sawyer HR, Moeller CL, Kozlowski GP. Immunocytochemical localization of neurophysin and oxytocin in ovine corpora lutea. Biol Reprod 1986;34:543-8.
DOI: https://doi.org/10.1095/biolreprod34.3.543
Ruiz-Palmero I, Hernando M, Garcia-Segura LM, Arevalo MA. G protein-coupled estrogen receptor is required for the neuritogenic mechanism of 17beta-estradiol in developing hippocampal neurons. Mol Cell Endocrinol 2013;372:105-15.
DOI: https://doi.org/10.1016/j.mce.2013.03.018
Viglietti-Panzica C, Aste N, Balthazart J, Panzica GC. Vasotocinergic innervation of sexually dimorphic medial preoptic nucleus of the male Japanese quail: influence of testosterone. Brain Res 1994;657:171-84.
DOI: https://doi.org/10.1016/0006-8993(94)90965-2
Wolstenholme JT, Taylor JA, Shetty SR, Edwards M, Connelly JJ, Rissman EF. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS One 2011;6:e25448.
DOI: https://doi.org/10.1371/journal.pone.0025448
Patisaul HB. Achieving CLARITY on bisphenol A, brain and behaviour. J Neuroendocrinol 2020;32:e12730.
DOI: https://doi.org/10.1111/jne.12730
Prins GS, Patisaul HB, Belcher SM, Vandenberg LN. CLARITY-BPA academic laboratory studies identify consistent low-dose Bisphenol A effects on multiple organ systems. Basic Clin Pharmacol Toxicol 2019;125:14-31.
DOI: https://doi.org/10.1111/bcpt.13125
Vandenberg LN, Hunt PA, Gore AC. Endocrine disruptors and the future of toxicology testing - lessons from CLARITY-BPA. Nat Rev Endocrinol 2019;15:366-74.
DOI: https://doi.org/10.1038/s41574-019-0173-y
Kumar D, Thakur MK. Anxiety like behavior due to perinatal exposure to bisphenol-A is associated with decrease in excitatory to inhibitory synaptic density of male mouse brain. Toxicology 2017;378:107-13.
DOI: https://doi.org/10.1016/j.tox.2017.01.010
Xu X, Dong F, Yang Y, Wang Y, Wang R, Shen X. Sex-specific effects of long-term exposure to bisphenol-A on anxiety- and depression-like behaviors in adult mice. Chemosphere 2015;120:258-66.
DOI: https://doi.org/10.1016/j.chemosphere.2014.07.021
Naule L, Picot M, Martini M, Parmentier C, Hardin-Pouzet H, Keller M, et al. Neuroendocrine and behavioral effects of maternal exposure to oral bisphenol A in female mice. J Endocrinol 2014;220:375-88.
DOI: https://doi.org/10.1530/JOE-13-0607
Picot M, Naule L, Marie-Luce C, Martini M, Raskin K, Grange-Messent V, et al. Vulnerability of the neural circuitry underlying sexual behavior to chronic adult exposure to oral bisphenol a in male mice. Endocrinology 2014;155:502-12.
DOI: https://doi.org/10.1210/en.2013-1639
Wolstenholme JT, Goldsby JA, Rissman EF. Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav 2013;64:833-9.
DOI: https://doi.org/10.1016/j.yhbeh.2013.09.007
Panzica GC, Bo E, Martini MA, Miceli D, Mura E, Viglietti-Panzica C, et al. Neuropeptides and enzymes are targets for the action of endocrine disrupting chemicals in the vertebrate brain. J Toxicol Environ Health B Crit Rev 2011;14:449-72.
DOI: https://doi.org/10.1080/10937404.2011.578562
Neumann ID. Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol 2008;20:858-65.
DOI: https://doi.org/10.1111/j.1365-2826.2008.01726.x
Heinrichs M, Domes G. Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog Brain Res 2008;170:337-50.
DOI: https://doi.org/10.1016/S0079-6123(08)00428-7
Witchey SK, Fuchs J, Patisaul HB. Perinatal bisphenol A (BPA) exposure alters brain oxytocin receptor (OTR) expression in a sex- and region- specific manner: A CLARITY-BPA consortium follow-up study. Neurotoxicology 2019;74:139-48.
DOI: https://doi.org/10.1016/j.neuro.2019.06.007
Rubin BS. Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol 2011;127:27-34.
DOI: https://doi.org/10.1016/j.jsbmb.2011.05.002
Kanaya M, Higo S, Ozawa H. Neurochemical characterization of neurons expressing estrogen receptor beta in the hypothalamic nuclei of rats using in situ hybridization and immunofluorescence. Int J Mol Sci 2019;21:115.
DOI: https://doi.org/10.3390/ijms21010115
Vida B, Hrabovszky E, Kalamatianos T, Coen C, Liposits Z, Kalló I. Oestrogen receptor alpha and beta immunoreactive cells in the suprachiasmatic nucleus of mice: distribution, sex differences and regulation by gonadal hormones. J Neuroendocrinol 2008;20:1270-7.
DOI: https://doi.org/10.1111/j.1365-2826.2008.01787.x
Grassi D, Bellini MJ, Acaz-Fonseca E, Panzica G, Garcia-Segura LM. Estradiol and testosterone regulate arginine-vasopressin expression in SH-SY5Y human female neuroblastoma cells through estrogen receptors-alpha and -beta. Endocrinology 2013;154:2092-100.
DOI: https://doi.org/10.1210/en.2012-2137
Grassi D, Ghorbanpoor S, Acaz-Fonseca E, Ruiz-Palmero I, Garcia-Segura LM. The selective estrogen receptor modulator raloxifene regulates arginine-vasopressin gene expression in human female neuroblastoma cells through G protein-coupled estrogen receptor and ERK signaling. Endocrinology 2015;1563706-16.
DOI: https://doi.org/10.1210/en.2014-2010
Lagunas N, Marraudino M, de Amorim M, Pinos H, Collado P, Panzica G, et al. Estrogen receptor beta and G protein-coupled estrogen receptor 1 are involved in the acute estrogenic regulation of arginine-vasopressin immunoreactive levels in the supraoptic and paraventricular hypothalamic nuclei of female rats. Brain Res 2019;1712:93-100.
DOI: https://doi.org/10.1016/j.brainres.2019.02.002
Rattan S, Zhou C, Chiang C, Mahalingam S, Brehm E, Flaws JA. Exposure to endocrine disruptors during adulthood: consequences for female fertility. J Endocrinol 2017;233:R109-29.
DOI: https://doi.org/10.1530/JOE-17-0023
Lopez-Rodriguez D, Franssen D, Sevrin E, Gerard A, Balsat C, Blacher S, et al. Persistent vs transient alteration of folliculogenesis and estrous cycle after neonatal vs adult exposure to bisphenol A. Endocrinology 2019;160:2558-72.
DOI: https://doi.org/10.1210/en.2019-00505
Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci 2018;19:453-69.
DOI: https://doi.org/10.1038/s41583-018-0026-z
Zheng X, Zhang K, Zhao Y, Fent K. Environmental chemicals affect circadian rhythms: An underexplored effect influencing health and fitness in animals and humans. Environ Int 2021;149:106159.
DOI: https://doi.org/10.1016/j.envint.2020.106159
Hatcher KM, Royston SE, Mahoney MM. Modulation of circadian rhythms through estrogen receptor signaling. Eur J Neurosci 2020;51:217-28.
DOI: https://doi.org/10.1111/ejn.14184
Liu J, Scira J, Donaldson S, Kajiji N, Dash GH, Donaldson ST. Sex and trait anxiety differences in psychological stress are modified by environment. Neuroscience 2018;383:178-90.
DOI: https://doi.org/10.1016/j.neuroscience.2018.04.027
Daviu N, Fuzesi T, Rosenegger DG, Rasiah NP, Sterley TL, Peringod G, et al. Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection. Nat Neurosci 2020;23:398-410.
DOI: https://doi.org/10.1038/s41593-020-0591-0
Biag J, Huang Y, Gou L, Hintiryan H, Askarinam A, Hahn JD, et al. Cyto- and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6J male mouse: a study of immunostaining and multiple fluorescent tract tracing. J Comp Neurol 2012;520:6-33.
DOI: https://doi.org/10.1002/cne.22698
Panagiotidou E, Zerva S, Mitsiou DJ, Alexis MN, Kitraki E. Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats. J Endocrinol 2014;220:207-18.
DOI: https://doi.org/10.1530/JOE-13-0416
Hadjimarkou MM, Vasudevan N. GPER1/GPR30 in the brain: Crosstalk with classical estrogen receptors and implications for behavior. J Steroid Biochem Mol Biol 2018;176:57-64.
DOI: https://doi.org/10.1016/j.jsbmb.2017.04.012
Ervin KS, Lymer JM, Matta R, Clipperton-Allen AE, Kavaliers M, Choleris E. Estrogen involvement in social behavior in rodents: Rapid and long-term actions. Horm Behav 2015;74:53-76.
DOI: https://doi.org/10.1016/j.yhbeh.2015.05.023
Ervin KS, Mulvale E, Gallagher N, Roussel V, Choleris E. Activation of the G protein-coupled estrogen receptor, but not estrogen receptor alpha or beta, rapidly enhances social learning. Psychoneuroendocrinology 2015;58:51-66.
DOI: https://doi.org/10.1016/j.psyneuen.2015.04.002
Acconcia F, Pallottini V, Marino M. Molecular mechanisms of action of BPA. Dose Response 2015;13:1559325815610582.
DOI: https://doi.org/10.1177/1559325815610582
Rajagopal S, Shenoy SK. GPCR desensitization: Acute and prolonged phases. Cell Signal 2018;41:9-16.
DOI: https://doi.org/10.1016/j.cellsig.2017.01.024
How to Cite
Bonaldo, B., Casile, A., Bettarelli, M., Gotti, S., Panzica, G., & Marraudino, M. (2021). Effects of chronic exposure to bisphenol A in adult female mice on social behavior, vasopressin system, and estrogen membrane receptor (GPER1). European Journal of Histochemistry, 65(s1). https://doi.org/10.4081/ejh.2021.3272
Copyright (c) 2021 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
