title: Protein-restricted diet during pregnancy after insemination alters behavioral phenotypes of the progeny.
abstract: BACKGROUND
  Epidemiological studies suggest that hyponutrition during the fetal period increases the risk of mental disorders such as attention deficit hyperactivity disorder and autism-spectrum disorder, which has been experimentally supported using animal models. However, previous experimental hyponutrition or protein-restricted (PR) diets affected stages other than the fetal stage, such as formation of the egg before insemination, milk composition during lactation, and maternal nursing behavior.
  
  
  RESULTS
  We conducted in vitro fertilization and embryo transfer in mice and allowed PR diet and folic acid-supplemented PR diet to affect only fetal environments. Comprehensive phenotyping of PR and control-diet progenies showed moderate differences in fear/anxiety-like, novelty-seeking, and prosocial behaviors, irrespective of folic-acid supplementation. Changes were also detected in gene expression and genomic methylation in the brain.
  
  
  CONCLUSIONS
  These results suggest that epigenetic factors in the embryo/fetus influence behavioral and epigenetic phenotypes of progenies. Significant epigenetic alterations in the brains of the progenies induced by the maternal-protein restriction were observed in the present study. To our knowledge, this is first study to evaluate the effect of maternal hyponutrition on behavioral phenotypes using reproductive technology.
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Furuse
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8510 Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohda
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kaneda
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan.
authors.forename: Takae
authors.initials: T
authors.lastname: Hirasawa
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yamada
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kushida
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Misho
authors.initials: M
authors.lastname: Kashimura
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8510 Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Ishino
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Japan mouse clinic, RIKEN BRC, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
keywords: Behavioral phenotypes; Gene expression and DNA methylation; In vitro fertilization; Maternal nutrition