Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 10 No. 1 February 01, 2023 p.7-20
Original Article
Paternal exposure to methylphenidate induces ADHD-like behavioral phenotypes and altered gene expressions in mouse offspring
  • Satoshi Numazawa (Division of Toxicology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy /
Ryota Nakano , Asuka Kaizaki-Mitsumoto , Satoshi Numazawa
Division of Toxicology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy
Keywords: Methylphenidate, Paternal, ADHD, Behavior, Next generation, POHaD

Methylphenidate (MPH) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). Because the onset of ADHD appears in early childhood and the incidence number is increasing, more patients could become adults with long-term use of MPH. In addition, few men would discontinue the medication during a fertile period. Recently, environmental factors such as diet and drug abuse have been reported to produce changes in the sperm epigenome and affect the health of the next generation. However, the effects of long-term administration of a psychostimulant such as MPH on the next generation is unknown. In this study, we examined the effects of paternal administration of MPH on the growth, behavior, and gene expression in offspring using a mouse model. Sires were subcutaneously administered MPH for 21 days and mated with naive dams. Upon reaching 6–7 weeks of age, offspring were subjected to spontaneous locomotor, elevated plus-maze, and passive avoidance tests. Additionally, RNA-seq and RT-qPCR were performed on the striatum. Paternal MPH exposure induced increased atomoxetine-sensitive impulsivity and decreased long-term memory function in the offspring. Enrichment analysis following RNA-seq revealed significant enrichment of terms involved in the nervous system. Gene expression levels of Snap25, Syt1, Drd2, Maoa, and Comt, which are associated with ADHD pathology, are altered in the striatum. These results suggest that continuous administration of MPH to male mice induces ADHD-like behavior and changes in the expression of genes involved in the nervous system in the brain of the next generation.