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Minoru Yoshida,¹ Natsuki Shimizu,² Megumi Suzuki,² Chiho Watanabe,³ Masahiko Satoh,⁴ Kouki Mori,⁵ and Akira Yasutake⁶

¹Faculty of Human Health Sciences, Hachinohe University, Hachinohe, Japan; ²Department of Chemistry, Meisei University, Hino, Tokyo, Japan; ³Department of Human Ecology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; ⁴Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, Nagoya, Japan; ⁵Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; ⁶Biochemistry Section, National Institute for Minamata Disease, Minamata, Kumamoto, Japan

Abstract
Background: Although a long latency period of toxicity after exposure to methylmercury (MeHg) is known to exist in humans, few animal studies have addressed this issue. Substantiation of delayed MeHg toxicity in animals would affect the risk evaluation of MeHg.

Objectives: Our goal in this study was to demonstrate the existence of a latency period in a rodent model in which the toxicity of perinatal MeHg exposure becomes apparent only later in life. Our study included metallothionein (MT) knockout mice because studies have suggested the potential susceptibility of this strain to the neurodevelopmental toxicity of MeHg.

Methods: Pregnant MT-null and wild-type C57Bl/6J mice were exposed to MeHg through their diet containing 5 µg Hg/g during gestation and early lactation. We examined behavioral functions of the offspring using frequently used paradigms, including open field behavior (OPF) , passive avoidance (PA) , and the Morris water maze (MM) , at ages of 12–13 and 52–53 weeks.

Results: At 12 weeks of age, behavioral effects of MeHg were not detected, except for OPF performance in MeHg-exposed MT-null females. At 52 weeks of age, the MeHg-exposed groups showed poorer performance both in PA and MM, and their OPF activity differed from controls. These effects of MeHg appeared exaggerated in the MT-null strain. The brain Hg concentration had leveled off by 13 weeks of age.

Conclusions: The results suggest the existence of a long latency period after perinatal exposure to low-level MeHg, in which the behavioral effects emerged long after the leveling-off of brain Hg levels. Hence, the initial toxicologic event responsible for the late effects should have occurred before this leveling-off of brain Hg.

Key words: behavioral effects, latency, methylmercury, mice, perinatal exposure. Environ Health Perspect 116: 746–751 (2008) . doi:10.1289/ehp.10906 available via http://dx.doi.org/ [Online 26 February 2008]

Address correspondence to C. Watanabe, Department of Human Ecology, Graduate School of Medicine, University of Tokyo, Hongo 7–3-1, Bunkyo-ku, Tokyo, 113–0033, Japan. Telephone: 81358413531. Fax: 81358413395. E-mail: chiho@humeco.m.u-tokyo.ac.jp

We thank C. Tohyama (University of Tokyo) and J.S. Suzuki (National Institute for Environmental Studies) for providing the MT-I/II knockout mice.

Part of this work was supported by the grant-in-aid of the Ministry of Health, Labor, and Wealth and of the Ministry of Education, Culture, Science, Sports and Technology.

The authors declare they have no competing financial interests.

Received 21 September 2007 ; accepted 25 February 2008.