Fundamental Toxicological Sciences

2019 - Vol. 6 No. 5

2019 - Vol. 6

Methylmercury causes neuronal cell death via M1-microglial activation in organotypic slices prepared from mouse cerebral cortex Vol.6, No.5, p.167-170
Takayuki Hoshi , Takashi Toyama , Akira Naganuma , Gi-Wook Hwang
Released: July 02, 2019
Abstract Full Text PDF[2M]

Methylmercury is an environmental pollutant that causes central nervous system injury. We reported that the expression of the inflammatory cytokines TNF-α and IL-1β was specifically induced in the brains of methylmercury-treated mice. In addition, we recently found that cytotoxic microglia (M1-microglia) may be involved in the induction of inflammatory cytokine expression by methylmercury in mouse cerebral slice cultures. In the current study, we investigated the involvement of M1-microglia in the neuronal cell death caused by methylmercury using mouse cerebral slice cultures. The results revealed that methylmercury activated steady state microglia (M0-microglia) to M1-microglia, but this activation was suppressed by pretreatment with minocycline, a microglial activation inhibitor. In addition, under the same conditions, minocycline suppressed neuronal cell death by methylmercury. These results suggest that methylmercury may induce neuronal cell death via activation to M1-microglia.

Original Article
Comprehensive toxicity evaluation of cyclopentyl methyl ether (CPME) for establishing a permitted daily exposure level Vol.6, No.5, p.145-165
Kaoru Inoue , Hiroshi Suzuki , Takashi Yamada
Released: June 25, 2019
Abstract Full Text PDF[1017K]

Cyclopentyl methyl ether (CPME, CAS No. 5614-37-9) is used as an alternative to other ethereal solvents in pharmaceutical chemical process development. Although brief summaries on the repeated dose toxicity or genotoxicity of CPME are available, no detailed toxicity information has been reported. This study performed a detailed hazard characterization of CPME using new reproductive/developmental toxicity data and existing data for a 28-day repeated dose toxicity and genotoxicity study of CPME. Sprague-Dawley (SD) rats were treated with CPME by gavage at doses of 50, 150, or 450 mg/kg/day in the reproductive/developmental toxicity study or at doses of 15, 150, and 700 mg/kg/day in the 28-day study. In the reproductive/developmental toxicity study, lower body weight in males and longer gestational lengths were observed in the F0 animals receiving the 450 mg/kg/day dose. In the F1 animals, lower body weight gain during days 1-7 of life was detected in the 450 mg/kg/day groups in both sexes. In the 28-day study, 6 of 10 males showed poor clinical conditions, resulting in unscheduled deaths in the 700 mg/kg/day group. Based on these findings, the NOAELs for both the reproductive/developmental and 28-day repeated dose toxicity studies were estimated at 150 mg/kg/day. The results of all genotoxicity studies including the bacterial reverse mutation test, in vitro mammalian cell chromosome aberration test, and in vivo mouse micronucleus test were negative. A permitted daily exposure (PDE) of 15 mg/day was suggested based on the present findings to help determine the PDE for the ICH guidelines on impurities in pharmaceuticals.