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Transient aberration of neuronal development in the hippocampal dentate gyrus after developmental exposure to brominated flame retardants in rats

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Abstract

We immunohistochemically investigated the impact and reversibility of three brominated flame retardants (BFRs) known to be weak thyroid hormone disruptors on neuronal development in the hippocampal formation and apoptosis in the dentate subgranular zone. Pregnant Sprague–Dawley rats were exposed to 10, 100, or 1,000 ppm decabromodiphenyl ether (DBDE); 100, 1,000 or 10,000 ppm tetrabromobisphenol A (TBBPA) or 1,2,5,6,9,10-hexabromocyclododecane (HBCD) in the diet from gestational day 10 through to day 20 after delivery (weaning). On postnatal day (PND) 20, interneurons in the dentate hilus–expressing reelin increased with all chemicals, suggestive of aberration of neuronal migration. However, this increase had disappeared by PND 77. NeuN-positive mature neurons increased in the hilus on PND 77 with all chemicals. In the subgranular zone on PND 20, an increase in apoptotic bodies suggestive of impaired neurogenesis was observed after exposure to TBBPA or HBCD. The effects on neuronal development were detected at doses of ≥100 ppm DBDE; ≥1,000 ppm TBBPA; and at least at 10,000 ppm HBCD. On PND 20, the highest dose of DBDE and HBCD revealed mild fluctuations in the serum concentrations of thyroid-related hormones suggestive of weak developmental hypothyroidism, while TBBPA did not. Thus, DBDE and TBBPA may exert direct effect on neuronal development in the brain, but hypothyroidism may be operated for DBDE and HBCD at high doses. An excess of mature neurons in the hilus at later stages may be the signature of the developmental effects of BFRs. However, the effect itself was reversible.

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Abbreviations

BFRs:

Brominated flame retardants

BW:

Body weight

CA1:

Cornu ammonis 1

DBDE:

Decabromodiphenyl ether

EphA5:

Ephrin type A receptor 5

GABA:

γ-Aminobutyric acid

GAD67:

Glutamic acid decarboxylase 67

GD:

Gestational day

HBCD:

1,2,5,6,9,10-Hexabromocyclododecane

NeuN:

Neuron-specific nuclear protein

PND:

Postnatal day

SGZ:

Subgranular zone

Tacr3:

Tachykinin receptor 3

TBBPA:

Tetrabromobisphenol A

TH:

Thyroid hormone

T3 :

Triiodothyronine

T4 :

Thyroxine

TSH:

Thyroid-stimulating hormone

References

  • Akaike M, Kato N, Ohno H, Kobayashi T (1991) Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317–322

    Article  PubMed  CAS  Google Scholar 

  • Alvarez-Dolado M, Ruiz M, Del Río JA, Alcántara S, Burgaya F, Sheldon M, Nakajima K, Bernal J, Howell BW, Curran T, Soriano E, Muñoz A (1999) Thyroid hormone regulates reelin and dab1 expression during brain development. J Neurosci 19:6979–6993

    PubMed  CAS  Google Scholar 

  • Bansal R, Zoeller RT (2008) Polychlorinated biphenyls (Aroclor 1254) do not uniformly produce agonist actions on thyroid hormone responses in the developing rat brain. Endocrinology 149:4001–4008

    Article  PubMed  CAS  Google Scholar 

  • Birnbaum LS, Staskal DF (2004) Brominated flame retardants: cause for concern? Environ Health Perspect 112:9–17

    Article  PubMed  CAS  Google Scholar 

  • Bowyer JF, Latendresse JR, Delongchamp RR, Muskhelishvili L, Warbritton AR, Thomas M, Tareke E, McDaniel LP, Doerge DR (2008) The effects of subchronic acrylamide exposure on gene expression, neurochemistry, hormones, and histopathology in the hypothalamus-pituitary-thyroid axis of male Fischer 344 rats. Toxicol Appl Pharmacol 230:208–215

    Article  PubMed  CAS  Google Scholar 

  • Chengelis CP (2001) A 90-day oral (gavage) toxicity study of HBCD in rats. WIL-186012. Brominated Flame Retardant Industry Panel. Chemical Manufacturers Association, Arlington, VA

  • Comer CP, Norton S (1982) Effects of perinatal methimazole exposure on a developmental test battery for neurobehavioral toxicity in rats. Toxicol Appl Pharmacol 63:133–141

    Article  PubMed  CAS  Google Scholar 

  • Cooper MA, Crockett DP, Nowakowski RS, Gale NW, Zhou R (2009) Distribution of EphA5 receptor protein in the developing and adult mouse nervous system. J Comp Neurol 514:310–328

    Article  PubMed  CAS  Google Scholar 

  • D’Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T (1997) Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J Neurosci 17:23–31

    PubMed  Google Scholar 

  • de Wit CA (2002) An overview of brominated flame retardants in the environment. Chemosphere 46:583–624

    Article  PubMed  Google Scholar 

  • Ema M, Fujii S, Hirata-Koizumi M, Matsumoto M (2008) Two-generation reproductive toxicity study of the flame retardant hexabromocyclododecane in rats. Reprod Toxicol 25:335–351

    Article  PubMed  CAS  Google Scholar 

  • Eriksson P, Fischer C, Wallin M, Jakobsson E, Fredriksson A (2006) Impaired behaviour, learning and memory, in adult mice neonatally exposed to hexabromocyclododecane (HBCDD). Environ Toxicol Pharmacol 21:317–322

    Article  PubMed  CAS  Google Scholar 

  • Frotscher M, Haas CA, Förster E (2003) Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold. Cereb Cortex 13:634–640

    Article  PubMed  Google Scholar 

  • Fujimoto H, Woo GH, Inoue K, Takahashi M, Hirose M, Nishikawa A, Shibutani M (2011) Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation. Reprod Toxicol 31:86–94

    Article  PubMed  CAS  Google Scholar 

  • Germer S, Piersma AH, van der Ven L, Kamyschnikow A, Fery Y, Schmitz HJ, Schrenk D (2006) Subacute effects of the brominated flame retardants hexabromocyclododecane and tetrabromobisphenol A on hepatic cytochrome P450 levels in rats. Toxicology 218:229–236

    Article  PubMed  CAS  Google Scholar 

  • Gong C, Wang TW, Huang HS, Parent JM (2007) Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci 27:1803–1811

    Article  PubMed  CAS  Google Scholar 

  • Goodman JE (2009) Neurodevelopmental effects of decabromodiphenyl ether (BDE-209) and implications for the reference dose. Regul Toxicol Pharmacol 54:91–104

    Article  PubMed  CAS  Google Scholar 

  • Hass U, Wamberg C (2002) Developmental neurotoxicity study of the brominated flame retardant tetrabromobisphenol A in rats. Reprod Toxicol 16:412 Abstract for 30th conference of the European teratology society, Hanover, 7th–11th September 2002

    Google Scholar 

  • Hoareau C, Hazane F, Le Pen G, Krebs MO (2006) Postnatal effect of embryonic neurogenesis disturbance on reelin level in organotypic cultures of rat hippocampus. Brain Res 1097:43–51

    Article  PubMed  CAS  Google Scholar 

  • Hopert AC, Beyer A, Frank K, Strunck E, Wunsche W, Vollmer G (1998) Characterization of estrogenicity of phytoestrogens in an endometrial-derived experimental model. Environ Health Perspect 106:581–586

    Article  PubMed  CAS  Google Scholar 

  • Houser CR (2007) Interneurons of the dentate gyrus: an overview of cell types, terminal fields and neurochemical identity. Prog Brain Res 163:217–232

    Article  PubMed  CAS  Google Scholar 

  • Ibhazehiebo K, Iwasaki T, Kimura-Kuroda J, Miyazaki W, Shimokawa N, Koibuchi N (2011a) Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced Purkinje cell dendrite arborization by polybrominated diphenyl ethers. Environ Health Perspect 119:168–175

    Article  PubMed  CAS  Google Scholar 

  • Ibhazehiebo K, Iwasaki T, Xu M, Shimokawa N, Koibuchi N (2011b) Brain-derived neurotrophic factor (BDNF) ameliorates the suppression of thyroid hormone-induced granule cell neurite extension by hexabromocyclododecane (HBCD). Neurosci Lett 493:1–7

    Article  PubMed  CAS  Google Scholar 

  • Ibhazehiebo K, Iwasaki T, Shimokawa N, Koibuchi N (2011c) 1,2,5,6,9,10-αHexabromocyclododecane (HBCD) impairs thyroid hormone-induced dendrite arborization of Purkinje cells and suppresses thyroid hormone receptor-mediated transcription. Cerebellum 10:22–31

    Article  PubMed  CAS  Google Scholar 

  • Kitamura S, Kato T, Iida M, Jinno N, Suzuki T, Ohta S, Fujimoto N, Hanada H, Kashiwagi K, Kashiwagi A (2005) Anti-thyroid hormonal activity of tetrabromobisphenol A, a flame retardant, and related compounds: affinity to the mammalian thyroid hormone receptor, and effect on tadpole metamorphosis. Life Sci 76:1589–1601

    Article  PubMed  CAS  Google Scholar 

  • Kundakovic M, Chen Y, Guidotti A, Grayson DR (2009) The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol Pharmacol 75:342–354

    Article  PubMed  CAS  Google Scholar 

  • Lavado-Autric R, Ausó E, García-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G (2003) Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073–1082

    PubMed  CAS  Google Scholar 

  • Lilienthal H, Verwer CM, van der Ven LT, Piersma AH, Vos JG (2008) Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: neurobehavioral effects in offspring from a one-generation reproduction study. Toxicology 246:45–54

    Article  PubMed  CAS  Google Scholar 

  • Lussier AL, Caruncho HJ, Kalynchuk LE (2009) Repeated exposure to corticosterone, but not restraint, decreases the number of reelin-positive cells in the adult rat hippocampus. Neurosci Lett 460:170–174

    Article  PubMed  CAS  Google Scholar 

  • Masutomi N, Shibutani M, Takagi H, Uneyama C, Takahashi N, Hirose M (2003) Impact of dietary exposure to methoxychlor, genistein, or diisononyl phthalate during the perinatal period on the development of the rat endocrine/reproductive systems in later life. Toxicology 192:149–170

    Article  PubMed  CAS  Google Scholar 

  • Meerts IATM, Assink Y, Cenijn PH, Weijers BM, van den Berg JHJ, Bergman Å, Koeman JH, Brouwer A (1999) Distribution of the flame retardant tetrabromobisphenol A in pregnant and fetal rats and effect on thyroid hormone homeostasis. Organohalogen Compd 40:375–378

    CAS  Google Scholar 

  • Nakajima A, Saigusa D, Tetsu N, Yamakuni T, Tomioka Y, Hishinuma T (2009) Neurobehavioral effects of tetrabromobisphenol A, a brominated flame retardant, in mice. Toxicol Lett 189:78–83

    Article  PubMed  CAS  Google Scholar 

  • Numachi Y, Yoshida S, Yamashita M, Fujiyama K, Toda S, Matsuoka H, Kajii Y, Nishikawa T (2007) Altered EphA5 mRNA expression in rat brain with a single methamphetamine treatment. Neurosci Lett 424:116–121

    Article  PubMed  CAS  Google Scholar 

  • Nuñez JL, McCarthy MM (2004) Cell death in the rat hippocampus in a model of prenatal brain injury: time course and expression of death-related proteins. Neuroscience 129:393–402

    Article  PubMed  Google Scholar 

  • Ogawa B, Ohishi T, Wang L, Takahashi M, Taniai E, Hayashi H, Mitsumori K, Shibutani M (2011) Disruptive neuronal development by acrylamide in the hippocampal dentate hilus after developmental exposure in rats. Arch Toxicol 85:987–994

    Article  PubMed  CAS  Google Scholar 

  • Porterfield SP (2000) Thyroidal dysfunction and environmental chemicals—potential impact on brain development. Environ Health Perspect 108(Suppl 3):433–438

    PubMed  CAS  Google Scholar 

  • Rice DC, Reeve EA, Herlihy A, Zoeller RT, Thompson WD, Markowski VP (2007) Developmental delays and locomotor activity in the C57BL6/J mouse following neonatal exposure to the fully-brominated PBDE, decabromodiphenyl ether. Neurotoxicol Teratol 29:511–520

    Article  PubMed  CAS  Google Scholar 

  • Saegusa Y, Fujimoto H, Woo GH, Inoue K, Takahashi M, Mitsumori K, Hirose M, Nishikawa A, Shibutani M (2009) Developmental toxicity of brominated flame retardants, tetrabromobisphenol A and 1,2,5,6,9,10-hexabromocyclododecane, in rat offspring after maternal exposure from mid-gestation through lactation. Reprod Toxicol 28:456–467

    Article  PubMed  CAS  Google Scholar 

  • Saegusa Y, Woo G-H, Fujimoto H, Inoue K, Takahashi M, Hirose M, Igarashi K, Kanno J, Mitsumori K, Nishikawa A, Shibutani M (2010a) Gene expression profiling and cellular distribution of molecules with altered expression in the hippocampal CA1 region after developmental exposure to anti-thyroid agents in rats. J Vet Med Sci 72:187–195

    Article  PubMed  CAS  Google Scholar 

  • Saegusa Y, Woo G-H, Fujimoto H, Kemmochi S, Shimamoto K, Hirose M, Mitsumori K, Nishikawa A, Shibutani M (2010b) Sustained production of Reelin-expressing interneurons in the hippocampal dentate hilus after developmental exposure to anti-thyroid agents in rats. Reprod Toxicol 29:407–414

    Article  PubMed  CAS  Google Scholar 

  • Salthun-Lassalle B, Traver S, Hirsch EC, Michel PP (2005) Substance P, neurokinins A and B, and synthetic tachykinin peptides protect mesencephalic dopaminergic neurons in culture via an activity-dependent mechanism. Mol Pharmacol 68:1214–1224

    Article  PubMed  CAS  Google Scholar 

  • Schoonover CM, Seibel MM, Jolson DM, Stack MJ, Rahman RJ, Jones SA, Mariash CN, Anderson GW (2004) Thyroid hormone regulates oligodendrocyte accumulation in developing rat brain white matter tracts. Endocrinology 145:5013–5020

    Article  PubMed  CAS  Google Scholar 

  • Shibutani M, Woo G-H, Fujimoto H, Saegusa Y, Takahashi M, Inoue K, Hirose M, Nishikawa A (2009) Assessment of developmental effects of hypothyroidism in rats from in utero and lactation exposure to anti-thyroid agents. Reprod Toxicol 28:297–307

    Article  PubMed  CAS  Google Scholar 

  • Smith PW, Dawson LA (2008) Neurokinin 3 (NK3) receptor modulators for the treatment of psychiatric disorders. Recent Pat CNS Drug Discov 3:1–15

    Article  PubMed  CAS  Google Scholar 

  • Stein T, Cosimo E, Yu X, Smith PR, Simon R, Cottrell L, Pringle MA, Bell AK, Lattanzio L, Sauter G, Lo Nigro C, Crook T, Machesk LM, Gusterson BA (2010) Loss of reelin expression in breast cancer is epigenetically controlled and associated with poor prognosis. Am J Pathol 177:2323–2333

    Article  PubMed  CAS  Google Scholar 

  • Tseng LH, Li MH, Tsai SS, Lee CW, Pan MH, Yao WJ, Hsu PC (2008) Developmental exposure to decabromodiphenyl ether (PBDE 209): effects on thyroid hormone and hepatic enzyme activity in male mouse offspring. Chemosphere 70:640–647

    Article  PubMed  CAS  Google Scholar 

  • van der Ven LT, Verhoef A, van de Kuil T, Slob W, Leonards PE, Visser TJ, Hamers T, Herlin M, Håkansson H, Olausson H, Piersma AH, Vos JG (2006) A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats. Toxicol Sci 94:281–292

    Article  PubMed  Google Scholar 

  • van der Ven LT, Van de Kuil T, Verhoef A, Verwer CM, Lilienthal H, Leonards PE, Schauer UM, Cantón RF, Litens S, De Jong FH, Visser TJ, Dekant W, Stern N, Håkansson H, Slob W, Van den Berg M, Vos JG, Piersma AH (2008) Endocrine effects of tetrabromobisphenol-A (TBBPA) in Wistar rats as tested in a one-generation reproduction study and a subacute toxicity study. Toxicology 245:76–89

    Article  PubMed  Google Scholar 

  • Viberg H, Fredriksson A, Jakobsson E, Orn U, Eriksson P (2003) Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. Toxicol Sci 76:112–120

    Article  PubMed  CAS  Google Scholar 

  • Viberg H, Fredriksson A, Eriksson P (2007) Changes in spontaneous behaviour and altered response to nicotine in the adult rat, after neonatal exposure to the brominated flame retardant, decabrominated diphenyl ether (PBDE 209). Neurotoxicology 28:136–142

    Article  PubMed  CAS  Google Scholar 

  • Vijverberg HP, van den Berg M (2004) Re: Viberg H et al. (2003) Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. Toxicol Sci 76, 112–120. Toxicol Sci 79:205–206

    Article  PubMed  CAS  Google Scholar 

  • Yamada-Okabe T, Sakai H, Kashima Y, Yamada-Okabe H (2005) Modulation at a cellular level of the thyroid hormone receptor-mediated gene expression by 1,2,5,6,9,10-hexabromocyclododecane (HBCD), 4,4′-diiodobiphenyl (DIB), and nitrofen (NIP). Toxicol Lett 155:127–133

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Blomgren K, Kuhn HG, Cooper-Kuhn CM (2009) Effects of postnatal thyroid hormone deficiency on neurogenesis in the juvenile and adult rat. Neurobiol Dis 34:366–374

    Article  PubMed  Google Scholar 

  • Zhang W, Cai Y, Sheng G, Chen D, Fu J (2011) Tissue distribution of decabrominated diphenyl ether (BDE-209) and its metabolites in sucking rat pups after prenatal and/or postnatal exposure. Toxicology 283:49–54

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Miss Tomomi Morikawa for her technical assistance in conducting the animal studies. We also thank Mrs. Shigeko Suzuki for her technical assistance in preparing the histological specimens. This work was supported in part by Health and Labour Sciences Research Grants (Research on Risk of Chemical Substances) from the Ministry of Health, Labour and Welfare of Japan. All authors disclose that there are no conflicts of interest that could inappropriately influence the outcome of the present study.

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Authors and Affiliations

  1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan

    Yukie Saegusa, Takumi Ohishi, Liyun Wang, Kunitoshi Mitsumori & Makoto Shibutani

  2. Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu, 501-1193, Japan

    Yukie Saegusa

  3. Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Hitoshi Fujimoto, Gye-Hyeong Woo & Makoto Shibutani

  4. Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Akiyoshi Nishikawa

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  1. Yukie Saegusa
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  2. Hitoshi Fujimoto
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  3. Gye-Hyeong Woo
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  4. Takumi Ohishi
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  5. Liyun Wang
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  6. Kunitoshi Mitsumori
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Correspondence to Makoto Shibutani.

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Saegusa, Y., Fujimoto, H., Woo, GH. et al. Transient aberration of neuronal development in the hippocampal dentate gyrus after developmental exposure to brominated flame retardants in rats. Arch Toxicol 86, 1431–1442 (2012). https://doi.org/10.1007/s00204-012-0824-4

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