Neuroendocrine disruption by bisphenol A and/or di(2-ethylhexyl) phthalate after prenatal, early postnatal and lactational exposure

Abstract

Bisphenol A (BPA) and di(2-ethylhexyl)phthalate (DEHP) are abundant endocrine disrupting chemicals (EDCs). In recent years, studies showed that EDCs may lead to neurodevelopmental diseases. The effects of prenatal exposure to these chemicals may have serious consequences. Moreover, exposure to EDCs as a mixture may have different effects than individual exposures. The present study aimed to determine the toxicity of BPA and/or DEHP on central nervous system (CNS) and neuroendocrine system in prenatal and lactational period in Sprague-Dawley rats. Pregnant rats were randomly divided into four groups: control (received vehicle); BPA group (received BPA at 50 mg/kg/day); DEHP group (received DEHP at 30 mg/kg/day); and combined exposure group (received both BPA at 50 mg/kg/day and DEHP at 30 mg/kg/day) during pregnancy and lactation by oral gavage. At the end of lactation, male offspring (n = 6) were randomly grouped. The alterations in the brain histopathology, neurotransmitter levels and enzyme activities in the cerebrum region, oxidative stress markers, and apoptotic effects in the hippocampus region were determined at adulthood. The results showed that exposure to EDCs at early stages of life caused significant changes in lipid peroxidation, total GSH and neurotransmitter levels, and activities of neurotransmitter-related enzymes. Moreover, BPA and/or DEHP led to apoptosis and histopathologic alterations in the hippocampus. Therefore, we can suggest that changes in oxidant/antioxidant status, as well as in neurotransmitters and related enzymes, can be considered as the underlying neurotoxicity mechanisms of BPA and DEHP. However, more mechanistic studies are needed.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Adewale HB, Todd KL, Mickens JA, Patisaul HB (2011) The impact of neonatal bisphenol-A exposure on sexually dimorphic hypothalamic nuclei in the female rat. Neurotoxicology 32:38–49

    CAS  Article  Google Scholar 

  2. Amigo I, Traba J, Reuda CB (2016) Isolating brain mitochondria by differential centrifugation. Bio-protocol 6:1–7

    Google Scholar 

  3. Andrade AJM, Grande SW, Talsness CE, Grote K, Chahoud I (2006) A dose–response study following in utero and lactational exposure to di-(2-ethylhexyl)-phthalate (DEHP): non-monotonic dose–response and low dose effects on rat brain aromatase activity. Toxicology 227:185–192

    CAS  Article  Google Scholar 

  4. Arbuckle TE, Davis K, Boylan K, Fisher M, Fu J (2016) Bisphenol A, phthalates and lead and learning and behavioral problems in Canadian children 6–11 years of age: CHMS 2007–2009. Neurotoxicology 54:89–98

    CAS  Article  Google Scholar 

  5. Bauer M, Heinz A, Whybrow PC (2002) Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol Psychiatry 7:140–156

    CAS  Article  Google Scholar 

  6. Chen K, Holschneider DP, Wu W, Rebrin I, Shih JC (2004) A spontaneous point mutation produces monoamine oxidase A/B knock-out mice with greatly elevated monoamines and anxiety-like behavior. J Biol Chem 279:39645–39652

    CAS  Article  Google Scholar 

  7. Chen F, Zhou L, Bai Y, Zhou R, Chen L (2014) Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol a. Brain Res 1571:12–24

    CAS  Article  Google Scholar 

  8. Chiavegatto S, Izidio GS, Mendes-Lana A, Aneas I, Freitas TA, Torrao AS et al (2009) Expression of alpha-synuclein is increased in the hippocampus of rats with high levels of innate anxiety. Mol Psychiatry 14:894–905

    CAS  Article  Google Scholar 

  9. Colborn T (2004) Neurodevelopment and endocrine disruption. Environ Health Perspect 112:944–949

    CAS  Article  Google Scholar 

  10. Cox KH, Gatewood JD, Howeth C, Rissman EF (2010) Gestational exposure to bisphenol A and cross-fostering affect behaviors in juvenile mice. Horm Behav 58:754–761

    CAS  Article  Google Scholar 

  11. Dai Y, Yang Y, Xu X, Hu Y (2015) Effects of uterine and lactational exposure to di-(2-ethylhexyl) phthalate on spatial memory and NMDA receptor of hippocampus in mice. Horm Behav 71:41–48

    CAS  Article  Google Scholar 

  12. Devoto P, Flore G (2006) On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr Neuropharmacol 4:115–125

    CAS  Article  Google Scholar 

  13. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 30:293–342

    CAS  Article  Google Scholar 

  14. Eilam-Stock T, Serrano P, Frankfurt M, Luine V (2012) Bisphenol-A impairs memory and reduces dendritic spine density in adult male rats. Behav Neurosci 126:175–185

    CAS  Article  Google Scholar 

  15. El-Missiry MA, Othman AI, Al-Abdan MA, El-Sayed AA (2014) Melatonin ameliorates oxidative stress, modulates death receptor pathway proteins, and protects the rat cerebrum against bisphenol-A-induced apoptosis. J Neurol Sci 347:251–256

    CAS  Article  Google Scholar 

  16. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    CAS  Article  Google Scholar 

  17. Gorczyca W, Bruno S, Darzynkiewicz RJ, Gong JP, Darzynkiewicz Z (1992) DNA strand breaks occurring during apoptosis—their early insitu detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors. Int J Oncol 1:639–648

    CAS  Google Scholar 

  18. Gore AC (2010) Neuroendocrine targets of endocrine disruptors. Hormones (Athens) 9:16–27

    Article  Google Scholar 

  19. Grandjean P, Landrigan PJ (2014) Neurobehavioural effects of developmental toxicity. Lancet Neurol 13:330–338

    CAS  Article  Google Scholar 

  20. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139

    CAS  Article  Google Scholar 

  21. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    CAS  Article  Google Scholar 

  22. Harley KG, Gunier RB, Kogut K, Johnson C, Bradman A, Calafat AM, Eskenazi B (2013) Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children. Environ Res 126:43–50

    CAS  Article  Google Scholar 

  23. Honma T, Miyagawa M, Suda M, Wang RS, Kobayashi K, Sekiguchi S (2006) Effects of perinatal exposure to bisphenol A on brain neurotransmitters in female rat offspring. Ind Health 44:510–524

    CAS  Article  Google Scholar 

  24. Ipapo KN, Factor-Litvak P, Whyatt RM, Calafat AM, Diaz D, Perera F, Rauh V, Herbstman JB (2017) Maternal prenatal urinary phthalate metabolite concentrations and visual recognition memory among infants at 27 weeks. Environ Res 155:7–14

    CAS  Article  Google Scholar 

  25. Ishido M, Masuo Y, Suzuki JS, Oka S, Niki E, Morita M (2004) Dicyclohexylphthalate causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immuno reactivity. J Neurochem 91:69–76

    CAS  Article  Google Scholar 

  26. Kabir ER, Rahman MS, Rahman I (2015) A review on endocrine disruptors and their possible impacts on human health. Environ Toxicol Pharmacol 40:241–258

    CAS  Article  Google Scholar 

  27. Kabuto H, Amakawa M, Shishibori T (2004) Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci 74:2931–2940

    CAS  Article  Google Scholar 

  28. Khadrawy YA, Noor NA, Mourad IM, Aboul Ezz HS (2016) Neurochemical impact of bisphenol A in the hippocampus and cortex of adult male albino rats. Toxicol Ind Health 32:1711–1719

    CAS  Article  Google Scholar 

  29. Kitamura Y, Taniguchi T, Shimohama S (1999) Apoptotic cell death in neurons and glial cells: implications for Alzheimer’s disease. Jpn J Pharmacol 79:1–5

    CAS  Article  Google Scholar 

  30. Li XJ, Jiang L, Chen L, Chen HS, Li X (2013) Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure: a study in rats. Environ Toxicol Pharmacol 36:392–402

    CAS  Article  Google Scholar 

  31. Luo G, Wei R, Niu R, Wang C, Wang J (2013) Pubertal exposure to bisphenol A increases anxiety-like behavior and decreases acetylcholinesterase activity of hippocampus in adult male mice. Food Chem Toxicol 60:177–180

    CAS  Article  Google Scholar 

  32. MacLusky NJ, Hajszan T, Leranth C (2005) The environmental estrogen bisphenol A inhibits estradiol-induced hippocampal synaptogenesis. Environ Health Perspect 113:675–679

    CAS  Article  Google Scholar 

  33. Mahaboob Basha P, Radha MJ (2020) Gestational and lactational exposition to di-n-butyl phthalate increases neurobehavioral perturbations in rats: a three generational comparative study. Toxicol Rep 7:480–491

    CAS  Article  Google Scholar 

  34. Matilla-Dueñas A, Corral-Juan M, Rodríguez-Palmero Seuma A, Vilas D, Ispierto L, Morais S, Sequeiros J, Alonso I, Volpini V, Serrano-Munuera C, Pintos-Morell G, Álvarez R, Sánchez I (2017) Rare neurodegenerative diseases: clinical and genetic update. Adv Exp Med Biol 1031:443–496

    Article  Google Scholar 

  35. Matsuda S, Saika S, Amano K, Shimizu E, Sajiki J (2010) Changes in brain monoamine levels in neonatal rats exposed to bisphenol A at low doses. Chemosphere 78:894–906

    CAS  Article  Google Scholar 

  36. Matsuda S, Matsuzawa D, Ishii D, Tomizawa H, Sutoh C, Nakazawa K (2012) Effects of perinatal exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain. Prog Neuro-Psychopharmacol Biol Psychiatry 39:273–279

    CAS  Article  Google Scholar 

  37. McCaffrey KA, Jones B, Mabrey N, Weiss B, Swan SH, Patisaul HB (2013) Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation. Neurotoxicology 36:55–62

    CAS  Article  Google Scholar 

  38. McHugh PC, Buckley DA (2015) The structure and function of the dopamine transporter and its role in CNS diseases. Vitam Horm 98:339–369

    CAS  Article  Google Scholar 

  39. Meyer G (2001) Human neocortical development: the importance of embryonic and early fetal events. Neuroscientist 7:303–314

    CAS  Article  Google Scholar 

  40. Nakamura K, Itoh K, Yoshimoto K, Sugimoto T, Fushiki S (2010) Prenatal and lactational exposure to low-doses of bisphenol A alters brain monoamine concentration in adult mice. Neurosci Lett 484:66–70

    CAS  Article  Google Scholar 

  41. Negri-Cesi P, Colciago A, Pravettoni A, Casati L, Conti L, Celotti F (2008) Sexual differentiation of the rodent hypothalamus: hormonal and environmental influences. J Steroid Biochem Mol Biol 109:294–299

    CAS  Article  Google Scholar 

  42. Nohynek GJ, Borgert CJ, Dietrich D, Rozman KK (2013) Endocrine disruption: fact or urban legend? Toxicol Lett 223:295–305

    CAS  Article  Google Scholar 

  43. Ohno M, Hamada N, Yamakawa J, Noh J, Morri H, Ito K (1987) Myasthenia gravis associated with Graves’ disease in Japan. Jpn J Med 26:2–6

    CAS  Article  Google Scholar 

  44. Panagiotidou E, Zerva S, Mitsiou DJ, Alexis MN, Kitraki E (2014) Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats. J Endocrinol 220:207–218

    CAS  Article  Google Scholar 

  45. Parent AS, Naveau E, Gerard A, Bourguignon JP, Westbrook GL (2011) Early developmental actions of endocrine disruptors on the hypothalamus, hippocampus and cerebral cortex. J Toxicol Environ Health B Crit Rev 14:328–345

    CAS  Article  Google Scholar 

  46. Perera F, Roen Nolte EL, Wang Y, Margolis AE, Calafat AM, Wang S et al (2016) Bisphenol A exposure and symptoms of anxiety and depression among inner city children at 10–12 years of age. Environ Res 151:195–202

    CAS  Article  Google Scholar 

  47. Poimenova A, Markaki E, Rahiotis C, Kitraki E (2010) Corticosterone-regulated actions in the rat brain are affected by perinatal exposure to low dose of bisphenol a. Neuroscience 167:741–749

    CAS  Article  Google Scholar 

  48. Richard MJ, Portal B, Meo J, Coudray C, Hadjian A, Favier A (1992) Malondialdehyde kit evaluated for determining plasma and lipoprotein fractions that react with thiobarbituric acid. Clin Chem 38:704–709

    CAS  Article  Google Scholar 

  49. Rubin R, Watson PD, Duff MC, Coen NJ (2014) The role of the hippocampus in flexible cognition and social behavior. Front Hum Neurosci 742:1–15

    Google Scholar 

  50. Smith CA, Holahan MR (2014) Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to Di(2-Ethylhexyl) phthalate in male long Evans rats. PLoS One 9:1–9

    Google Scholar 

  51. Sullivan RM, Dufresne MM (2006) Mesocortical dopamine and HPA axis regulation: role of laterality and early environment. Brain Res 1076:49–59

    CAS  Article  Google Scholar 

  52. Tanida T, Warita K, Ishihara K, Fukui S, Mitsuhashi T, Sugawara T, Tabuchi Y, Nanmori T, Qi WM, Inamoto T, Yokoyama T, Kitagawa H, Hoshi N (2009) Fetal and neonatal exposure to three typical environmental chemicals with different mechanisms of action: mixed exposure to phenol, phthalate, and dioxin cancels the effects of sole exposure on mouse midbrain dopaminergic nuclei. Toxicol Lett 189:40–47

    CAS  Article  Google Scholar 

  53. Toiber D, Berson A, Greenberg D, Melamed-Book N, Diamant S, Soreq H (2008) N-Acetylcholinesterase-induced apoptosis in Alzheimer’s disease. PLoS One 3:1–12

    Article  CAS  Google Scholar 

  54. Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12

    Google Scholar 

  55. Wang R, Xu X, Weng H, Yan S, Sun Y (2016) Effects of early pubertal exposure to di-(2-ethylhexyl) phthalate on social behavior of mice. Horm Behav 80:117–124

    CAS  Article  Google Scholar 

  56. Wang Y, Du X, Wang D, Wang J, Du J (2020) Effects of bisphenol A exposure during pregnancy and lactation on hippocampal function in newborn rats. Int J Med Sci 17:1751–1762

    CAS  Article  Google Scholar 

  57. Waye A, Trudeau VL (2011) Neuroendocrıne dısruptıon: more than hormones are upset. J Toxicol Environ Health 14:270–291

    CAS  Article  Google Scholar 

  58. Woolf NJ, Butcher LL (2011) Cholinergic systems mediate action from movement to higher consciousness. Behav Brain Res 221:488–498

    CAS  Article  Google Scholar 

  59. Yan B, Guo J, Liu X, Li J, Yang X, Ma P, Wu Y (2016) Oxidative stress mediates dibutyl phthalate induced anxiety-like behavior in Kunming mice. Environ Toxicol Pharmacol 45:45–51

    CAS  Article  Google Scholar 

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Funding

This study was supported by Hacettepe University Scientific Projects Coordination Unit [Project no: TYL-2018-17006].

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Contributions

AY performed tissue preparation, measurement of neuroendocrine parameters and oxidative stress parameters, and TUNEL assay. GO performed dosing and euthanasia of animals, tissue preparation, and measurement of neuroendocrine parameters. AB performed dosing and euthanasia of animals and measurement of oxidative stress parameters. PE performed study conception and design, euthanasia of animals, tissue preparation, statistical analyses, and evaluation of results. NY performed histopathological examinations and TUNEL assay. NDZ performed histopathological examinations and TUNEL assay. BKG performed study conception and design, statistical analyses, evaluation of results, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Belma Kocer-Gumusel.

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The study was approved by Gazi University Animal Ethics Committee (G.U.ET–18.043).

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Yirun, A., Ozkemahli, G., Balci, A. et al. Neuroendocrine disruption by bisphenol A and/or di(2-ethylhexyl) phthalate after prenatal, early postnatal and lactational exposure. Environ Sci Pollut Res (2021). https://doi.org/10.1007/s11356-021-12408-9

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Keywords

  • Apoptosis
  • Bisphenol A
  • Di(2-ethylhexyl) phthalate
  • Endocrine disrupting chemicals
  • Lactational exposure
  • Neurotoxicity
  • Oxidative stress
  • Prenatal exposure