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Transient suppression of late-stage neuronal progenitor cell differentiation in the hippocampal dentate gyrus of rat offspring after maternal exposure to nicotine

  • Organ Toxicity and Mechanisms
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Abstract

To examine the developmental exposure effect of nicotine (NIC) on hippocampal neurogenesis, pregnant Sprague–Dawley rats were treated with (−)-NIC hydrogen tartrate salt through drinking water at 2, 10 or 50 ppm from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, immunohistochemically doublecortin (Dcx)+ cells increased at ≥10 ppm in the dentate subgranular zone (SGZ) as examined in male offspring; however, dihydropyrimidinase-like 3 (TUC4)+ cells decreased at 2 ppm, and T box brain 2 (Tbr2)+ cells were unchanged at any dose. Double immunohistochemistry revealed decreases in TUC4+/Dcx+ and TUC4+/Dcx− cells, an increase in TUC4−/Dcx+ cells at 2 and 10 ppm and an increase in Tbr2−/Dcx+ cells at 50 ppm, suggesting an increase in type-3 progenitor cells at ≥2 ppm and decrease in immature granule cells at 2 and 10 ppm. The number of mature neuron-specific NeuN− progenitor cells expressing nicotinic acetylcholine receptor α7 in the SGZ and mRNA levels of Chrna7 and Chrnb2 in the dentate gyrus was unchanged at any dose, suggesting a lack of direct nicotinic stimulation on progenitor cells. In the dentate hilus, glutamic acid decarboxylase 67+ interneurons increased at ≥10 ppm. All changes disappeared on PND 77. Therefore, maternal exposure to NIC reversibly affects hippocampal neurogenesis targeting late-stage differentiation in rat offspring. An increase in interneurons suggested that their activation affected granule cell differentiation. The lowest observed adverse effect level was at 2 ppm (0.091 mg/kg/day as a free base) by the affection of hippocampal neurogenesis at ≥2 ppm.

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Abbreviations

ACh:

Acetylcholine

Dcx:

Doublecortin

GAD67:

Glutamic acid decarboxylase 67

GABA:

γ-Aminobutyric acid

GD:

Gestational day

GFAP:

Glial fibrillary acidic protein

NAChR:

Nicotinic acetylcholine receptor

NeuN:

Neuron-specific nuclear protein

NIC:

Nicotine

PCNA:

Proliferating cell nuclear antigen

PND:

Postnatal day

SGZ:

Subgranular zone

Tbr2:

T box brain 2

TSH:

Thyroid-stimulating hormone

TUC4:

Dihydropyrimidinase-like 3

T3 :

Triiodothyronine

T4 :

Thyroxine

References

  • Abrous DN, Adriani W, Montaron MF, Aurousseau C, Rougon G, Le Moal M, Piazza PV (2002) Nicotine self-administration impairs hippocampal plasticity. J Neurosci 22:3656–3662

    CAS  PubMed  Google Scholar 

  • Benowitz NL (2008) Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83:531–541

    Article  CAS  PubMed  Google Scholar 

  • Benowitz NL (2010) Nicotine addiction. N Engl J Med 362:2295–2303

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bruel-Jungerman E, Lucassen PJ, Francis F (2011) Cholinergic influences on cortical development and adult neurogenesis. Behav Brain Res 221:379–388

    Article  CAS  PubMed  Google Scholar 

  • Colzani R, Fang SL, Alex S, Braverman LE (1998) The effect of nicotine on thyroid function in rats. Metabolism 47:154–157

    Article  CAS  PubMed  Google Scholar 

  • Frey BN, Andreazza AC, Nery FG, Martins MR, Quevedo J, Soares JC, Kapczinski F (2007) The role of hippocampus in the pathophysiology of bipolar disorder. Behav Pharmacol 18:419–430

    Article  PubMed  Google Scholar 

  • Gatzke-Kopp LM, Beauchaine TP (2007) Direct and passive prenatal nicotine exposure and the development of externalizing psychopathology. Child Psychiatry Hum Dev 38:255–269

    Article  PubMed Central  PubMed  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  CAS  PubMed  Google Scholar 

  • Hodge RD, Kowalczyk TD, Wolf SA, Encinas JM, Rippey C, Enikolopov G, Kempermann G, Hevner RF (2008) Intermediate progenitors in adult hippocampal neurogenesis: Tbr2 expression and coordinate regulation of neuronal output. J Neurosci 28:3707–3717

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Kanamori K, Takahashi S, Fujita K (2007) Effects of nicotine on embryos and fetuses of pregnant women who smoke: examination of single-sample urine and umbilical blood and state of smoking. J Hum Nurs Stud 5:39–47

    Google Scholar 

  • Kanamori K, Takahashi S, Fujita K (2008) Examination about nicotine density in the colostrum of the smoking pregnant woman. J Hum Nurs Stud 6:17–26

    Google Scholar 

  • Karaconji IB (2005) Facts about nicotine toxicity. Arh Hig Rada Toksikol 56:363–371

    PubMed  Google Scholar 

  • Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447–452

    Article  CAS  PubMed  Google Scholar 

  • Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, Horvat V, Volk B, Kempermann G (2010) Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE 5:e8809

    Article  PubMed Central  PubMed  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  CAS  PubMed  Google Scholar 

  • Liu JJ, Mohila CA, Gong Y, Govindarajan N, Onn SP (2005) Chronic nicotine exposure during adolescence differentially influences calcium-binding proteins in rat anterior cingulate cortex. Eur J Neurosci 22:2462–2474

    Article  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 −ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Lv J, Mao C, Zhu L, Zhang H, Pengpeng H, Xu F, Liu Y, Zhang L, Xu Z (2008) The effect of prenatal nicotine on expression of nicotine receptor subunits in the fetal brain. Neurotoxicology 29:722–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, Craig CR, Collins AC, Damaj MI, Donny EC, Gardiner PS, Grady SR, Heberlein U, Leonard SS, Levin ED, Lukas RJ, Markou A, Marks MJ, McCallum SE, Parameswaran N, Perkins KA, Picciotto MR, Quik M, Rose JE, Rothenfluh A, Schafer WR, Stolerman IP, Tyndale RF, Wehner JM, Zirger JM (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 190:269–319

    Article  CAS  PubMed  Google Scholar 

  • Mullen RJ, Buck CR, Smith AM (1992) NeuN a neuronal specific nuclear protein in vertebrates. Development 116:201–211

    CAS  PubMed  Google Scholar 

  • OECD Test Guideline 426. OECD Guideline for Testing of Chemicals. Developmental Neurotoxicity Study. Organisation for Economic Co-operation and Development, Paris, France; (2007). Available at http://www.oecdbookshop.org/oecd/display.asp?K=5L4FG25MNKXS&lang=EN&sort=sortdate%2Fd&sf1=Title&st1=neurotoxicity&sf3=SubjectCode&st4=not+E4+or+E5+or+P5&sf4=SubVersionCode&ds=neurotoxicity%3B+All+Subjects%3B+&m=1&dc=4&plang=en. Accessed 5 January 2013

  • Ogawa B, Wang L, Ohishi T, Taniai E, Akane H, Suzuki K, Mitsumori K, Shibutani M (2012) Reversible aberration of neurogenesis targeting late-stage progenitor cells in the hippocampal dentate gyrus of rat offspring after maternal exposure to acrylamide. Arch Toxicol 86:779–790

    Article  CAS  PubMed  Google Scholar 

  • Ohishi T, Wang L, Ogawa B, Fujisawa K, Taniai E, Hayashi H, Mitsumori K, Shibutani M (2010) No effect of sustained systemic growth retardation on the distribution of Reelin-expressing interneurons in the neuron-producing hippocampal dentate gyrus in rats. Reprod Toxicol 30:591–599

    Article  CAS  PubMed  Google Scholar 

  • Pawluski JL, Brummelte S, Barha CK, Crozier TM, Galea LA (2009) Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Front Neuroendocrinol 30:343–357

    Article  CAS  PubMed  Google Scholar 

  • Pérez-Stable EJ, Herrera B, Jacob P 3rd, Benowitz NL (1998) Nicotine metabolism and intake in black and white smokers. JAMA 280:152–156

    Article  PubMed  Google Scholar 

  • Pontikides N, Krassas GE (2002) Influence of cigarette smoking on thyroid function, goiter formation and autoimmune thyroid disorders. Hormones 1:91–98

    Article  PubMed  Google Scholar 

  • Saegusa Y, Woo G-H, Fujimoto H, Kemmochi S, Shimamoto K, Hirose M, Mitsumori K, Nishikawa A, Shibutani M (2010) 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  CAS  PubMed  Google Scholar 

  • Sato N, Hatakeyama S, Shimizu N, Hikima A, Aoki J, Endo K (2001) MR evaluation of the hippocampus in patients with congenital malformations of the brain. AJNR Am J Neuroradiol 22:389–393

    CAS  PubMed  Google Scholar 

  • Schneider T, Bizarro L, Asherson PJ, Stolerman IP (2010) Gestational exposure to nicotine in drinking water: teratogenic effects and methodological issues. Behav Pharmacol 21:206–216

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shibutani M, Uneyama C, Miyazaki K, Toyoda K, Hirose M (2000) Methacarn fixation: a novel tool for analysis of gene expressions in paraffin-embedded tissue specimens. Lab Invest 80:199–208

    Article  CAS  PubMed  Google Scholar 

  • Slotkin TA, Southard MC, Adam SJ, Cousins MM, Seidler FJ (2004) Alpha7 nicotinic acetylcholine receptors targeted by cholinergic developmental neurotoxicants: nicotine and chlorpyrifos. Brain Res Bull 64:227–235

    Article  CAS  PubMed  Google Scholar 

  • Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T (2005) GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47:803–815

    Article  CAS  PubMed  Google Scholar 

  • US Environmental Protection Agency (US EPA) (1991) Pesticide Assessment Guidelines. Subdivision F, Hazard evaluation: human and domestic animals, Addendum 10, Neurotoxicity series 81, 82, and 83. Health effects division, office of pesticide program

  • Van Nassauw L, Wu M, De Jonge F, Adriaensen D, Timmermans JP (2005) Cytoplasmic, but not nuclear, expression of the neuronal nuclei (NeuN) antibody is an exclusive feature of Dogiel type II neurons in the guinea-pig gastrointestinal tract. Histochem Cell Biol 124:369–377

    Article  PubMed  Google Scholar 

  • Wakschlag LS, Pickett KE, Cook E Jr, Benowitz NL, Leventhal BL (2002) Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review. Am J Public Health 92:966–974

    Article  PubMed  Google Scholar 

  • Wang L, Ohishi T, Shiraki A, Morita R, Akane H, Ikarashi Y, Mitsumori K, Shibutani M (2012) Developmental exposure to manganese chloride induces sustained aberration of neurogenesis in the hippocampal dentate gyrus of mice. Toxicol Sci 127:508–521

    Article  CAS  PubMed  Google Scholar 

  • Wierońska JM, Brański P, Siwek A, Dybala M, Nowak G, Pilc A (2010) GABAergic dysfunction in mGlu7 receptor-deficient mice as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and increased reelin proteins in the hippocampus. Brain Res 1334:12–24

    Article  PubMed  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 

Download references

Acknowledgments

The authors thank Ms. Shigeko Suzuki for her technical assistance in preparing the histological specimens. This work was supported by Health and Labour Sciences Research Grants (Research on Risk of Chemical Substances) from the Ministry of Health, Labour and Welfare of Japan.

Conflict of interest

The authors disclose that there are no competing financial interests that could inappropriately influence the outcome of this 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

    Takumi Ohishi, Liyun Wang, Hirotoshi Akane, Ayako Shiraki, Megu Itahashi, Kunitoshi Mitsumori & Makoto Shibutani

  2. Gotemba Laboratory, Bozo Research Center Inc., 1284 Kamado, Gotemba, Shizuoka, 412-0039, Japan

    Takumi Ohishi

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

    Ayako Shiraki & Megu Itahashi

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  1. Takumi Ohishi
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  2. Liyun Wang
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  3. Hirotoshi Akane
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Correspondence to Makoto Shibutani.

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Ohishi, T., Wang, L., Akane, H. et al. Transient suppression of late-stage neuronal progenitor cell differentiation in the hippocampal dentate gyrus of rat offspring after maternal exposure to nicotine. Arch Toxicol 88, 443–454 (2014). https://doi.org/10.1007/s00204-013-1100-y

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