Open Access

Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse

  • Midori Shimizu1,
  • Hitoshi Tainaka2,
  • Taro Oba1,
  • Keisuke Mizuo2,
  • Masakazu Umezawa1 and
  • Ken Takeda1, 2Email author
Particle and Fibre Toxicology20096:20

DOI: 10.1186/1743-8977-6-20

Received: 1 April 2009

Accepted: 29 July 2009

Published: 29 July 2009

Abstract

Background

Nanotechnology is developing rapidly throughout the world and the production of novel man-made nanoparticles is increasing, it is therefore of concern that nanomaterials have the potential to affect human health. The purpose of this study was to investigate the effects of maternal exposure to nano-sized anatase titanium dioxide (TiO2) on gene expression in the brain during the developmental period using cDNA microarray analysis combined with Gene Ontology (GO) and Medical Subject Headings (MeSH) terms information.

Results

Analysis of gene expression using GO terms indicated that expression levels of genes associated with apoptosis were altered in the brain of newborn pups, and those associated with brain development were altered in early age. The genes associated with response to oxidative stress were changed in the brains of 2 and 3 weeks old mice. Changes of the expression of genes associated with neurotransmitters and psychiatric diseases were found using MeSH terms.

Conclusion

Maternal exposure of mice to TiO2 nanoparticles may affect the expression of genes related to the development and function of the central nervous system.

Background

Nanotechnology and the production of novel man-made nanoparticles are increasing worldwide. Titanium dioxide (TiO2) has a high level of photocatalytic activity, and can be used for air and water purification and self-cleaning surfaces [1]. The activity level of nanoparticles is higher than that of bulk-sized particles [2, 3]. TiO2 has the potential to produce reactive oxygen species (ROS) in its photocatalysis [1] and its possibly detrimental health effects are of concern. It has been reported that a mixture of anatase and rutile TiO2 nanoparticles induced cytotoxicity against human lung epithelial cells (BEAS-2B), even in the absence of photoactivation [4]. Sayes et al. [5] showed that anatase TiO2 nanoparticles, which can generate more ROS than rutile TiO2 particles, exhibited a higher level of cytotoxicity against human dermal fibroblasts and human lung epithelial cells (A549) than rutile TiO2 nanoparticles.

The small size of nanoparticles can bestow unique translocational properties [6, 7]. It has been reported that nanosized elemental carbon particles (36 nm) inhaled by adult rats were translocated into extrapulmonary organs, such as liver [8]. A subsequent study showed that intranasally instilled carbon black nanoparticles can be translocated to the central nervous system, including cerebrum, cerebellum, and olfactory bulb via the olfactory nerve [9]. In a recent study, Takeda et al. [10] found that TiO2 nanoparticles administrated subcutaneously to pregnant mice were transferred from the mother to the fetal brain, and induced apoptosis in the mitral cells of the olfactory bulb of mice exposed maternally to the nanoparticles. Fetal brains are easily affected by blood-borne substances, including nano-sized materials, to a much greater extent than adult brains because the development of the blood-brain barrier in the fetal brains is incomplete [11]. Taking these observations into consideration, functional alterations of the central nervous system induced by maternal exposure to nanoparticles need to be investigated. To analyze the effect of maternal exposure to TiO2 nanoparticles on the early stages of development of the brain, we used microarray technology and gene expression profiles by functional annotation of genes using Gene Ontology (GO) terms and Medical Subject Headings (MeSH) terms.

Methods

Titanium dioxide nanoparticles

TiO2 nanopowder (particle size 25-70 nm; surface area 20-25 m2/g; crystal form anatase) was purchased from Sigma-Aldrich Japan Inc. (Tokyo, Japan) and used as TiO2 nanoparticles. The nanopowder was suspended in saline (Otsuka Pharmaceutical Factory Inc., Tokushima, Japan) with 0.05% (v/v) Tween 80 and sonicated for more than 30 minutes immediately before administration.

Animals and treatments

Pregnant ICR mice, purchased from Japan SLC Inc. (Shizuoka, Japan), were housed in a room under controlled temperature (23 ± 1°C), humidity (55 ± 5%) and light (12 h light/12 h dark cycle with light on at 8:00 a.m.) with ad libitum access to food and water. Pregnant mice were transported carefully to minimize stress factors by Sankyo Labo Service Co., Inc (Tokyo, Japan). All animals were handled in accordance with institutional and national guidelines for the care and use of laboratory animals.

A 100 μL volume of TiO2 suspended at 1 μg/μL was injected subcutaneously into pregnant mice (n = 15) on gestational days 6, 9, 12, and 15 for the exposure group, while 100 μL of vehicle alone was injected into pregnant mice (n = 14) as a control group. Brain tissue was obtained from male fetuses on embryonic day (ED) 16 (n = 8/group) and from male pups on postnatal days 2 (n = 10/group), 7 (n = 10/group), 14 (n = 9/group), and 21 (n = 9/group).

Total RNA extraction

Whole brains were immediately frozen in liquid nitrogen and kept at -80°C. Frozen tissue was homogenized and extracted with Isogen (Nippon Gene Co., Ltd., Tokyo, Japan) while well stirred by a Vortex-Genie 2 (Scientific Industries, Tokyo, Japan). Total RNA was isolated according to the manufacture's protocol and suspended in TE buffer (10 mM Tris-HCl, pH 8.0, 1 mM EDTA).

Complementary DNA microarray analysis

RNAs for microarray analysis were pooled for each group, purified using the RNeasy Micro Kit (Qiagen, Hilden, Germany) and reverse-transcribed to yield complementary DNA (cDNA) labeled with the fluorescent dye Cy3 or Cy5 using the SuperScript Indirect cDNA Labeling Core Kit (Invitrogen, CA, USA) and the SuperScript Indirect cDNA Labeling System Purification Kit (Invitrogen). Cy3- and Cy5-labeled samples were purified using the CyScribe GFX Purification Kit (GE Healthcare Bio-Sciences, Little Chalfont, UK). The generated targets were mixed and subjected to hybridization to an NIA mouse 15 K Microarray v2.0 (AGC Techno Glass Co. Ltd., Chiba, Japan) consisting of 16,192 gene probes. Microarrays were scanned with two different photomultiplier sensitivities by a ScanArray (Packard BioChip Technologies, MA, USA). The scanner output images were normalized and signal quantification was performed using ScanArray Express (Perkin Elmer, MA, USA) and TIBCO Spotfire (TIBCO Software Inc., CA, USA). Normalization was used so that the overall intensity ratio of Cy3 and Cy5 was equal to 1. Statistical analysis was done with analysis of variance (ANOVA) and the level of statistical significance was set at P < 0.05.

Functional analysis of microarray data with gene annotation

A total of 37 GO terms and 66 MeSH terms associated with anatomy, brain development and associated peptides, neurotransmitters, hormones, behavior and psychological phenomena, brain related disorders, oxidative stress, inflammation, and cell death were selected (Table 1, 2); and 2838 and 3625 genes were annotated by GO and MeSH terms, respectively, using the gene reference database PubGene (https://​server.​pubgene.​com/​online/​PubGene/​, Pub Gene AS, Oslo, NOR). These annotations were updated in April, 2008. The genes for which upregulation and downregulation were detected were categorized with GO and MeSH terms. The enrichment factor for each category was defined as (nf/n)/(Nf/N), where nf is the number of differentially expressed genes within the category, n is the total number of genes within that same category, Nf is the number of differentially expressed genes on the entire microarray, and N is the total number of genes on the microarray. Statistical analysis was performed using Fisher's exact test with hypergeometric distribution and the level of statistical significance was set at P < 0.05.
Table 1

List of GO terms selected for gene annotation

Category

 

GO term

biological process

developmental process

brain development

  

   forebrain development

  

   midbrain development

  

   hindbrain development

  

generation of neurons

  

glial cell differentiation

 

biological regulation

cell death

  

   apoptosis

  

neuron apoptosis

  

activated T cell apoptosis

  

B cell apoptosis

  

negative regulation of neuron apoptosis

  

apoptotic mitochondrial changes

  

   induction of programmed cell death

  

induction of apoptosis

  

anti-apoptosis

  

glucocorticoid biosynthesis

  

glucocorticoid metabolism

  

neurotransmitter metabolism

  

neurotransmitter transport

 

multicellular organismal process

cognition

  

learning and, or memory

 

regulation of biological process

regulation of glial cell differentiation

  

regulation of nerve growth factor receptor activity

  

regulation of glucocorticoid biosynthesis process

 

cellular process

mitochondrial fission

  

mitochondrial fusion

 

response to stimulus

response to oxidative stress

  

   response to reactive oxygen species

  

response to superoxide

  

superoxide metabolism

  

glutathione biosynthesis

  

glutathione metabolism

molecular function

 

motor activity

  

superoxide dismutase activity

  

glucocorticoids receptor activity

  

brain derived neurotrophic factor binding

Table 2

List of MeSH terms selected for gene annotation

Category

MeSH term

 

Anatomy

Blood Brain Barrier

Neurons

 

Microglia

Olfactory Receptor Neurons

 

Mitochondria

Synapses

 

Neuroglia

 

Diseases

Alzheimer Disease

Inflammation

 

Anxiety Disorders

Learning Disorders

 

Attention Deficit Disorder

Memory Disorders

 

with Hyperactivity

Mitochondrial Disease

 

Autistic Disorder

Neurogenic Inflammation

 

Cognition Disorders

Parkinson Disease

 

Epilepsy

Schizophrenia

Psychiatry and Psychology

Affective Symptoms

Memory

 

Anxiety

Memory, Short-Term

 

Cognition

Motivation

 

Depression

Stress, Psychological

 

Emotions

 

Chemicals and Drugs

Apoptosis Inducing Factor

Anti-Anxiety Agents

 

Apoptosis Regulatory Proteins

Glutathione

 

Caspases

Glutathione Peroxidase

 

Brain Derived Neurotrophic

Glutathione Synthase

 

Factor

Inflammation Mediators

 

Glial Cell Line-Derived

Neuronal Apoptosis-

 

Neurotrophic Factor

Inhibitory Protein

 

Nerve Growth Factor

Nitric Oxide

 

Hormones

Reactive Oxygen Species

 

Glucocorticoids

Superoxides

 

Growth Hormone

Superoxide Dismutase

 

Thyroid Hormones

 

Neurotransmitters

Acetylcholine

Norepinephrine

 

Dopamine

Serotonin

 

Epinephrine

Receptors,

 

gamma-Aminobutyric Acid

Neurotransmitter

 

Glutamic Acid

Neuropeptides

  

Neurotransmitter Uptake

  

Inhibitors

Biological Science

Apoptosis

Motor Activity

 

Cell Death

Neural Plasticity

 

Gene, Mitochondrial

Oxidative Stress

 

Lipid Peroxides

 

Results

Analysis of cDNA microarrays

In the maternal TiO2 exposure group, the expression levels of 462 genes were changed significantly in the brain of the fetus at ED 16 (upregulation 229 genes; downregulation 233 genes), and those of 864 (upregulation 234; downregulation 630), 417 (upregulation 351; downregulation 66), 738 (upregulation 450; downregulation 288), and 1887 (upregulation 613; downregulation 1274) were changed significantly in the brain of offspring 2, 7, 14, and 21 days old, respectively (Table 3). The number of genes differentially expressed between groups was increased remarkably in the brain of 21 days old pups.
Table 3

The number of genes differentially expressed in maternal TiO2 exposure group

Age

Upregulated

Downregulated

Total

Embryonic day 16

229

233

462

2 days old

234

630

864

7 days old

351

66

417

14 days old

450

288

738

21 days old

613

1274

1887

Functional categorization of microarray data

Of the genes expressed differentially in the maternal TiO2 exposure group, 3, 2, 8, and 4 GO categories were enriched significantly in the brain at 2, 7, 14, and 21 days after birth, respectively (Table 4), while 6, 2, 36, and 28 MeSH categories were enriched significantly at 2, 7, 14, and 21 days after birth (Additional file 1). Eight MeSH categories were also enriched significantly in the fetal brain at ED 16 (Additional file 1). The largest group of GO categories enriched was those related to cell death 2 - 21 days after birth; 121 and 64 genes linked to apoptosis at 2 and 7 days after birth, respectively, and 92 and 173 genes linked to "cell death" were identified at 14 and 21 days after birth. "Brain development" was also a large category at 2 (34 genes) and 14 (43 genes) days after birth. GO categories related to oxidative stress, such as "superoxide dismutase activity", were also enriched significantly at 14 and 21 days after birth. The largest MeSH categories enriched were "Mitochondria" at ED 16 (31 genes) and 2 days (56 genes) after birth and "Apoptosis" at 14 (118 genes) and 21 (230 genes) days after birth. The "Mitochondria" category was persistently enriched at 14 (60 genes) and 21 (109 genes) days after birth. MeSH categories related to oxidative stress, such as "Glutathione", "Lipid Peroxidation", and "Reactive Oxygen Species", were also enriched significantly at ED 16 and 14 and 21 days after birth. MeSH categories related to inflammation and neurotransmitters including "Epinephrine", "Norepinephrine", "Serotonin", and "Glutamic Acid" were also highly enriched at 14 and 21 days after birth.
Table 4

Significantly enriched GO categories in maternal exposure group vs. control group

GO term

Enrichment factor

P value

Embryonic day 16

  

   (None)

  

2 days old

  

   apoptosis

1.04

.05

   brain development

1.21

.04

   motor activity

1.80

.02

7 days old

  

   apoptosis

1.11

.01

   glial cell differentiation

5.14

.02

14 days old

  

   activated T cell apoptosis

3.75

.02

   brain development

1.48

.00

   cell death

1.08

.04

   induction of apoptosis

1.28

.01

   motor activity

1.58

.05

   response to oxidative stress

1.70

.01

   response to reactive oxygen species

1.53

.05

   superoxide dismutase activity

2.22

.01

21 days old

  

   anti-apoptosis

1.58

.02

   cell death

1.03

.04

   glutathione biosynthesis

1.62

.04

   superoxide dismutase activity

1.75

.01

Discussion

Nanoparticles have a high level of reactivity with biological tissue, since they have a large specific surface area [6, 7]. It has been reported that fullerenes, which are manufactured carbon nanoparticles, induce oxidative stress in the brain of juvenile largemouth bass [12]. Tin-Tin-Win-Shwe et al. [13] showed that intranasal instillation of ultrafine carbon black (14 nm) to mice induced a higher level of expression of cytokines and chemokines in the olfactory bulb compared to those induced by the same mass of carbon black (95 nm). The particles used in the exposed pregnant mice group can enter the circulatory system and can transfer to and damage the fetus. Sugamata et al. [14] reported that the cytoplasmic granules of granular perithelial cells contain particles of diesel exhaust (DE) and degenerate in both the cerebral cortex and the hippocampus of mice exposed prenatally to DE. A later study [15] showed that maternal DE exposure alters the levels of monoamines and their metabolites in brains and spontaneous motor activity in male mice. Since TiO2 was detected in the brain of mice maternally exposed to TiO2 nanoparticles [10], which is the material used in this study, microarray was applied to the analysis of the effects of maternal exposure to TiO2 nanoparticles on the brain of neonatal mice.

In the present study, we used only male fetuses and pups for analysis because the prevalence of some psychiatric disorders in childhood, such as autism and attention deficit hyperactivity disorder, is higher in men than in women. The results of the microarray analysis showed changes in expression of hundreds of genes in the brain at ED 16, and at 2, 7, 14, and 21 days after birth. To interpret the large amount of data generated, functional categorization using GO terms and MeSH terms were performed, which identified potentially important categories on the basis of both a high enrichment factor (>1.00) and statistical significance (P < 0.05). MeSH is a controlled vocabulary thesaurus produced by the National Library of Medicine and used for indexing, cataloging, and searching for biomedical and health-related information and documents. Although most researchers use GO for providing annotation to genes, MeSH terms are proposed to be a useful complementary tool for interpretation of microarray data [16]. A subsequent report [17] showed that the use of MeSH has the advantage of producing anatomical and disease information with respect to the genes of interest. In the present study, genes were annotated with the terms related to anatomy, brain development, brain-related disorders, those associated with nanotoxicology (oxidative stress [6, 7, 12] and inflammation [6, 7, 13]), and those associated with the effects of maternal exposure to DE or TiO2 nanoparticles (hormones [18], behavior and neurotransmitters [15, 18], and cell death [10, 14, 19]) for analysis.

As a result, GO terms associated with development of brain were extracted at 2 and 14 days after birth, those associated with cell death, including apoptosis, were extracted 2 to 21 days after birth, and those associated with response to oxidative stress were extracted at 14 and 21 days. Brain development is regulated by neurotrophins such as nerve growth factor, brain-derived neurotrophic factor [20], and glial cell line-derived neurotrophic factor [21], and hormones including growth hormone [22] and thyroid hormone [23, 24]. Analysis using MeSH terms showed that alteration of these factors that can lead to abnormal development of the central nervous system was induced by maternal exposure to TiO2 nanoparticle. It has been reported that neuronal cell death, including apoptosis, is essential for elimination of neurons and axons to make correct synaptogenesis in the early stage of brain development [25, 26]. The result of functional analysis suggested that disruption of these processes can be caused by maternal exposure to TiO2 nanoparticles.

It has been reported that the changes of environment surrounding pregnant mice cause abnormal level of neurotransmitters in the brain of the offspring. Meyer et al. [27] reported that maternal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid causes abnormal fetal dopaminergic development, which is similar to a schizophrenic symptom. Maternal stress also induces altered expression of genes related to the dopaminergic system in the midbrain and causes hyperactivity in adult offspring [28]. The results that MeSH terms associated with neurotransmitters and motor activity were extracted suggest that maternal exposure to TiO2 nanoparticles causes abnormal levels of neurotransmitters that can lead to altered motor activity.

As for MeSH terms, those associated with diseases were extracted in the functional analysis. Some diseases such as autistic disorder, epilepsy, and learning disorders, occur in childhood, and although Alzheimer's disease, schizophrenia, and Parkinson's disease arise mainly in adulthood or old age, related MeSH terms were extracted in the results from infant mice of mothers exposed to TiO2. In the early 1990s, Dr David Barker J.P. stated that fetal undernutrition increases the incidence of cardiovascular disease in adult life [29]. Subsequent studies showed the environment that the fetus senses indirectly through the mother can be linked to other diseases in adulthood, and proposed a hypothesis of "early developmental origins of adult disease" [30]. The results of the present study suggest that maternal exposure to nanoparticles can alter gene expression in the neonatal period and might cause the onset of psychiatric disorders even in adulthood. However, the present study did not show how the maternal response to the nanoparticles altered the mother's behavior toward the pups and how this in turn altered gene expression. Further investigations are needed to clarify the critical factor for the gene expression change. Moreover, the changes caused by maternal exposure to TiO2 nanoparticles should not be limited to the brain. Our published [10] and unpublished data suggest that other organ systems are also affected.

Conclusion

This study showed that maternal exposure to anatase TiO2 nanoparticle caused the changes in the expression of genes associated with brain development, cell death, response to oxidative stress, and mitochondria in the brain during the perinatal period, and those associated with inflammation and neurotransmitters in the later stage (Figure 1). Further investigation is needed to clarify the alterations of neurotransmitter levels and motor function. This study showed also that analysis using microarray data with GO and MeSH terms can provide meaningful information, and will contribute to further interpretation of microarray results in toxicological research.
https://static-content.springer.com/image/art%3A10.1186%2F1743-8977-6-20/MediaObjects/12989_2009_Article_84_Fig1_HTML.jpg
Figure 1

Summary of the extracted terms with genes differentially expressed in the maternal TiO 2 exposure group.

Abbreviations

cDNA: 

complementally DNA

DE: 

diesel exhaust

ED: 

embryonic day

GO: 

Gene Ontology

MeSH: 

Medical Subject Headings

ROS: 

reactive oxygen species

TiO2

titanium dioxide.

Declarations

Acknowledgements

The authors thank Dr Tomomi Hishinuma of Research Center for Health Sciences of Nanoparticles, Tokyo University of Science for assistance in the microarray experiments, and Drs Masao Sugamata and Tomomi Ihara of Tochigi Institute of Clinical Pathology for valuable discussion. This work was supported in part by a Grant-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Gland-in Aid for the Private University Science Research Upgrade Promotion Business "Academic Frontier Project and a Grant-in Aid for Health and Labour Sciences Research Grants, Research on Risk of Chemical Substances, from the Ministry of Health, Labour and Welfare".

Authors’ Affiliations

(1)
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science
(2)
Research Center for Health Sciences of Nanoparticles, Research Institute for Science and Technology, Tokyo University of Science

References

  1. Fujishima A, Zhang X, Tryk DA: TiO 2 photocatalysis and related surface phenomena. Surf Sci Rep 2008, 63: 515–582. 10.1016/j.surfrep.2008.10.001View Article
  2. Beydoun D, Amal R, Low G, McEvoy S: Role of nanoparticles in photocatalysis. J Nanopart Res 1999, 1: 439–458. 10.1023/A:1010044830871View Article
  3. Jang HD, Kim SK, Kim SJ: Effect of particle size and phase composition of titanium dioxide nanoparticles on the photocatalytic properties. J Nanopart Res 2001, 3: 141–147. 10.1023/A:1017948330363View Article
  4. Gurr JR, Wang AS, Chen CH, Jan KY: Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. Toxicology 2005, 213: 66–73. 10.1016/j.tox.2005.05.007PubMedView Article
  5. Sayes CM, Wahi R, Kurian PA, Liu Y, West JL, Ausman KD, Warheit DB, Colvin VL: Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci 2006, 92: 174–185. 10.1093/toxsci/kfj197PubMedView Article
  6. Oberdörster G, Oberdörster E, Oberdörster J: Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Persp 2005, 113: 823–839.View Article
  7. Nel A, Xia T, Madler L, Li N: Toxic potential of materials at the nanolevel. Science 2006, 311: 622–627. 10.1126/science.1114397PubMedView Article
  8. Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C: Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 2002, 65: 1531–1543. 10.1080/00984100290071658PubMedView Article
  9. Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C: Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 2004, 16: 437–445. 10.1080/08958370490439597PubMedView Article
  10. Takeda K, Suzuki K, Ishihara A, Kubo-Irie M, Fujimoto R, Tabata M, Oshio S, Nihei Y, Ihara T, Sugamata M: Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 2009, 55: 95–102. 10.1248/jhs.55.95View Article
  11. Watson RE, Desesso JM, Hurtt ME, Cappon GD: Postnatal growth and morphological development of the brain: a species comparison. Birth Defects Res B Dev Reprod Toxicol 2006, 77: 471–484. 10.1002/bdrb.20090PubMedView Article
  12. Oberdörster E: Manufactured nanomaterials (fullerenes, C 60 ) induce oxidative stress in the brain of juvenile largemouth bass. Environ Health Persp 2004, 112: 1058–1062.View Article
  13. Tin-Tin-Win-Shwe , Yamamoto S, Ahmed S, Kakeyama M, Kobayashi T, Fujimaki H: Brain cytokine and chemokine mRNA expression in mice induced by intranasal instillation with ultrafine carbon black. Toxicol Lett 2006, 163: 153–160. 10.1016/j.toxlet.2005.10.006PubMedView Article
  14. Sugamata M, Ihara T, Takano H, Oshio S, Takeda K: Maternal diesel exhaust exposure damages newborn murine brains. J Health Sci 2006, 52: 82–84. 10.1248/jhs.52.82View Article
  15. Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I, Takeda K: Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci Lett 2009, 449: 38–41. 10.1016/j.neulet.2008.09.085PubMedView Article
  16. Nakazato T, Takinaka T, Mizuguchi H, Matsuda H, Bono H, Asogawa M: BioCompass: a novel functional inference tool that utilizes MeSH hierarchy to analyze groups of genes. In Silico Biol 2007, 8: 53–61.
  17. Umezawa M, Tanaka N, Tainaka H, Takeda K, Ihara T, Sugamata M: Microarray analysis provides insight into early steps of pathophysiology of mouse endometriosis model induced by autotransplantation of endometrium. Life Sci 2009, 84: 832–837. 10.1016/j.lfs.2009.03.015PubMedView Article
  18. Takeda K, Tsukue N, Yoshida S: Endocrine-disrupting activity of chemicals in diesel exhaust and diesel exhaust particles. Environ Sci 2004, 11: 33–45.PubMed
  19. Sugamata M, Ihara T, Sugamata M, Takeda K: Maternal exposure to diesel exhaust leads to pathological similarity to autism in newborns. J Health Sci 2006, 52: 486–488. 10.1248/jhs.52.486View Article
  20. Tucker KL, Meyer M, Barde YA: Neurotrophins are required for nerve growth during development. Nat Neurosci 2001, 4: 29–37. 10.1038/82868PubMedView Article
  21. Hellmich HL, Kos L, Cho ES, Mahon KA, Zimmer A: Embryonic expression of glial cell-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions. Mech Dev 1996, 54: 95–105. 10.1016/0925-4773(95)00464-5PubMedView Article
  22. Scheepens A, Möderscheim TA, Gluckman PD: The role of growth hormone in neural development. Horm Res 2005,64(Suppl 3):66–72. 10.1159/000089320PubMedView Article
  23. Dussault JH, Ruel J: Thyroid hormones and brain development. Annu Rev Physiol 1987, 49: 321–34. 10.1146/annurev.ph.49.030187.001541PubMedView Article
  24. Oppenheimer JH, Schwartz HL: Molecular basis of thyroid hormone-dependent brain development. Endocr Rev 1997, 18: 462–475. 10.1210/er.18.4.462PubMed
  25. Gordon N: Apoptosis (programmed cell death) and other reasons for elimination of neurons and axons. Brain Dev 1995, 17: 73–77. 10.1016/0387-7604(94)00109-BPubMedView Article
  26. Porter AG, Janicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999, 6: 99–104. 10.1038/sj.cdd.4400476PubMedView Article
  27. Meyer U, Engler A, Weber L, Schedlowski M, Feldon J: Preliminary evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. Neuroscience 2008, 154: 701–709. 10.1016/j.neuroscience.2008.04.031PubMedView Article
  28. Son GH, Chung S, Geum D, Kang SS, Choi WS, Kim K, Choi S: Hyperactivity and alteration of the midbrain dopaminergic system in maternally stressed male mice offspring. Biochem Biophys Res Commun 2007, 352: 823–829. 10.1016/j.bbrc.2006.11.104PubMedView Article
  29. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS: Fetal nutrition and cardiovascular disease in adult life. Lancet 1993, 341: 938–941. 10.1016/0140-6736(93)91224-APubMedView Article
  30. Xu G, Umezawa M, Takeda K: Early development origins of adult disease caused by malnutrition and environmental chemical substances. J Health Sci 2009, 55: 11–19. 10.1248/jhs.55.11View Article

Copyright

© Shimizu et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement