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

  • Midori Shimizu1,

    Affiliated with

    • Hitoshi Tainaka2,

      Affiliated with

      • Taro Oba1,

        Affiliated with

        • Keisuke Mizuo2,

          Affiliated with

          • Masakazu Umezawa1 and

            Affiliated with

            • Ken Takeda1, 2Email author

              Affiliated with

              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.
              http://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

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              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.

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