Title of Research:
20-3-02
Development of a short-term in vivo assay for thyroid hormone disrupting activity in maternal rats
and their fetus/pups as prescreening for developmental neurotoxicity potential.
Principal Investigator:
Tomoya Yamada, DVM, PhD (Fellow, Sumitomo Chemical Company, Ltd., Environmental HealthScience Laboratory)
3-1-98 Kasugadenaka, Konohanaku, Osaka 554-8558, Japan(e-mail) yamadat8@sc.sumitomo-chem.co.jp
Collaborators:
Hiroaki Aoyama, PhD (Executive Director, Toxicology Division, The Institute of EnvironmentalToxicology)
4321 Uchimoriya-machi, Joso-shi, Ibaraki 303-0043, Japan(e-mail) aoyama@iet.or.jp
Hidenori Suto, PhD (Research Associate, Sumitomo Chemical Company, Ltd., Environmental
Health Science Laboratory)
3-1-98 Kasugadenaka, Konohanaku, Osaka 554-8558, Japan(e-mail) sutoh@sc.sumitomo-chem.co.jp
Summary of Research:
As thyroid hormones (TH) are essential for fetal brain development, the chemicals which induce
reduction of serum TH levels may potentially interfere with the developing brain. Since
standardized studies to identify developmental neurotoxicity (DNT) require significant resources, asimple screening test is eagerly awaited for sorting chemicals to be examined in the DNT studies.
Recently, we began verifying the feasibility of a modified Comparative Thyroid Assay (CTA) bydownsizing the number of rats but with the addition of examination of the brain TH levels and brain
histology. The 1st study showed that the modified CTA could detect 6-propylthiouracil (6-PTU, 10ppm)-induced severe (>70%) reduction of serum TH in dams, with >50% suppressed serum/brain
TH levels and brain abnormality (heterotopia) in offspring. The modified CTA also detected sodium
phenobarbital (NaPB, 1000 ppm)-induced mild (<35%) reduction of serum TH levels in dams, withmild (<35%) reduction of serum/brain TH levels in fetuses but not in pups, and without increased
brain heterotopia. The 2nd study showed that the findings by NaPB at 1000 ppm were generally
reproducible in dams and offspring. To investigate what degree of serum/brain TH disruptions will
be adverse to brain morphology, we performed a 3rd study focusing on heterotopia formation byusing treatment with a wider range of doses of 6-PTU (0, 1, 3, and 10 ppm in feed) during thecritical time window for heterotopia formation (GD19-LD2). 6-PTU dose-dependently reduced
serum TH in dams and serum/brain TH in offspring, and induced heterotopia formation in PND21pups. Although detailed analysis is still in progress, our findings suggest that the modified CTA canbe a potential short-term in vivo assay for sorting offspring TH disruptors.
Timeline:
March 1, 2022 – February 28, 2023.
Topics:Oral presentation at JCIA LRI Annual Workshop 2021 “Development of a short-term in vivo assayfor thyroid hormone disrupting activity in maternal rats and their fetuses/pups as prescreening forpotential of developmental neurotoxicity.” (On-line, August 26th, 2022)
Publications:
Kenta Minami1, Hidenori Suto1, Akira Sato2, Keiko Ogata1, Tadashi Kosaka2, Hitoshi Hojo2,Naofumi Takahashi2, Naruto Tomiyama2, Takako Fukuda 1, Katsumasa Iwashita 1, Hiroaki
Aoyama2 and Tomoya Yamada1 (1 Sumitomo Chemical Company, Ltd. 2 The Institute ofEnvironmental Toxicology), 2023. Feasibility study for a downsized comparative thyroid assay withmeasurement of brain thyroid hormones and histopathology in rats: case study with
6-propylthiouracil and sodium phenobarbital at high dose. Regulatory Toxicology andPharmacology. 137, 105283.
Kenta Minami1, Akira Sato2, Naruto Tomiyama2, Keiko Ogata1, Tadashi Kosaka2, Hitoshi Hojo2,Naofumi Takahashi2, Hidenori Suto1, Hiroaki Aoyama2 and Tomoya Yamada1 (1 Sumitomo
Chemical Company, Ltd. 2 The Institute of Environmental Toxicology), 2023. Feasibility study for adownsized comparative thyroid assay with measurement of brain thyroid hormones andhistopathology in rats: Part II. Within laboratory reproducibility for effects of sodium phenobarbital(submitted, under review)
Kenta Minami1, 〇Hidenori Suto1, Akira Sato2, Keiko Ogata1, Kenta Minami1, Tadashi Kosaka2,Hitoshi Hojo2, Naofumi Takahashi2, Naruto Tomiyama2, Hiroaki Aoyama2, Tomoya Yamada1 (1Sumitomo Chemical Company, Ltd. 2 The Institute of Environmental Toxicology)“Feasibility and reliability of a downsized comparative thyroid assay for evaluating thyroid hormone
disrupting activity in maternal rats and their offspring: reproducibility study with sodiumphenobarbital”. The 49th Annual Meeting of the Japanese Society of Toxicology, Sapporo, Japan,July 2022.
Tomoya Yamada (Sumitomo Chemical Company, Ltd.)“Comparative Thyroid Assay: Current situation of a short-term in vivo assay for thyroid hormone
disrupting activity in maternal rats and their offspring as prescreening for potential developmentalneurotoxicity”. The 49th Annual Meeting of the Japanese Society of Toxicology, Sapporo, Japan,July 2022.
〇Keiko Ogata1, Kenta Minami1, Hidenori Suto1, Hiroyuki Asano1, Masahiko Kushida1, Keiko
Maeda1, Akira Sato2, Naofumi Takahashi2, Hiroaki Aoyama2, Tomoya Yamada1 (1 Sumitomo
Chemical Company, Ltd. 2 The Institute of Environmental Toxicology)“A method evaluating brain morphology in a screening study of low thyroid hormone-related
developmental neurotoxicity”. The 39th Annual Meeting of the Japanese Society of Toxicologic
pathology, Tokyo, Japan, January 2023.
〇Tomoya Yamada1 and Hiroaki Aoyama2, (1 Sumitomo Chemical Company, Ltd. 2 The Institute ofEnvironmental Toxicology)“A proposal for the use of a modified comparative thyroid assay with reduced number of animals
and additional parameters”. The 62nd Annual Meeting of the Society of Toxicology, Nashville,United States, To be presented on March 2023.
〇Kenta Minami1, Hidenori Suto1, Akira Sato2, Keiko Ogata1, Tadashi Kosaka2, Hitoshi Hojo2,Naofumi Takahashi2, Naruto Tomiyama2, Hiroaki Aoyama2, Tomoya Yamada1 (1 Sumitomo
Chemical Company, Ltd. 2 The Institute of Environmental Toxicology)“Effects of sodium phenobarbital in a downsized comparative thyroid assay with additional
examination of brain thyroid hormone levels and brain histology”. The 62nd Annual Meeting of theSociety of Toxicology, Nashville, United States, To be presented on March 2023.