Influence of acute exposure to a low dose of systemic insecticide fipronil on locomotor activity and emotional behavior in adult male mice

Fipronil (FPN) is a systemic insecticide that antagonizes the gamma-aminobutyric acid type A (GABAA) receptors in insects. Recently, adverse effects of FPN on mammals have been reported, but most of those were caused by high doses of FPN and additives in the products. We investigated the effects of low-dose pure FPN on the emotional behavior of mice. Nine-week-old male mice conducted behavioral tests 24 hr after FPN administration by gavage at doses of 0.05 or 5 mg/kg based on the no-observed-effect level (NOEL), showed a significant increase in locomotor activity and dose-dependent responses on the time they spent in the central zone in the open field test. Pure FPN below the NOEL dose may affect the emotional behavior of mice

Peripubertal exposure to the neonicotinoid pesticide dinotefuran affects dopaminergic neurons and causes hyperactivity in male mice

Although neonicotinoid pesticides are expected to have harmful influence on mammals, there is little animal experimental data to support the effect and mechanisms. Since acetylcholine causes the release of dopamine, neonicotinoids may confer a risk of developmental disorders via a disturbance in the monoamine systems. Male mice were peripubertally administered dinotefuran (DIN) referring to no observed effect level (NOEL) and performed behavioral and immunohistological analyses. In an open field test, the total locomotor activity was increased in a dose-dependent manner. The immunoreactivity of tyrosine hydroxylase in the substantia nigra was increased in DIN-exposed mice. These results suggest that exposure to DIN in peripubertal male mice causes hyperactivity and a disturbance of dopaminergic signaling

Musashi-1 Post-Transcriptionally Enhances Phosphotyrosine-Binding Domain-Containing m-Numb Protein Expression in Regenerating Gastric Mucosa

<div><h3>Objective</h3><p>Upregulation of the RNA-binding protein Musashi-1 (Msi1) has been shown to occur in rat gastric corpus mucosa after ethanol-induced mucosal injury. However, there is no direct evidence linking Msi1 with gastric regeneration. We examined the process of tissue repair after acute gastric mucosal injury with Msi1-knock-out (KO) mice to clarify the role of Msi1 and Msi1-dependent regulation of m-Numb expression in regenerating gastric mucosa.</p> <h3>Methods</h3><p>Acute gastric injury was induced in Msi1-KO and wild-type ICR mice by administering absolute ethanol. Expression of the splicing variants of <em>m-Numb</em> mRNA and protein in the gastric mucosa were analyzed by quantitative RT-PCR and western blotting, respectively.</p> <h3>Results</h3><p>We demonstrated that phosphotyrosine-binding domain-containing m-Numb expression was significantly upregulated at both the mRNA and protein levels in wild-type mice at 3 h after ethanol-induced acute gastric injury. In contrast, in Msi1-KO mice, the m-Numb protein was expressed weakly, and was associated with delayed regeneration of the injured gastric mucosal epithelium. In the Msi1-KO mouse, the ratio of <em>m-Numb</em> mRNA to total <em>m-Numb</em> mRNA in the heavy polysome fractions was lower than that in the wild-type mouse. Further, we showed that m-Numb-enhancement in gastric mucous cells induced the expression of prostate stem cell antigen and metallothionein-2. Under the m-Numb enhancing condition, the gastric cells exhibited enhanced cell proliferation and were significantly more resistant to H₂O₂-induced cell death than control cells.</p> <h3>Conclusions</h3><p>Msi1-dependent post-transcriptional enhancement of m-Numb is crucial in gastric epithelial regeneration.</p> </div

Schematic representation of Msi1-dependent gastric regeneration.

<p>After gastric damage, PTB domain-containing <i>m-numb</i> transcript is induced. Msi1 enhances the <i>m-numb</i> translation. The translated m-Numb protein induces the expression of regeneration-related genes such as <i>PSCA</i> and <i>Mt2</i>, resulting in gastric regeneration.</p

m-Numb-induced expression of regeneration-related genes.

<p>(A) Expression of <i>LGR5</i>, <i>DCLK1</i>, <i>PSCA</i>, and <i>Mt2</i> mRNA in the stomachs of sham-treated wild-type (white bars) and Msi1-KO (black bars) mice. **<i>P</i><0.01 compared to wild-type mice. (B) mRNA expression of total <i>m-numb</i>, <i>LGR5</i>, <i>DCLK1</i>, <i>PSCA</i>, and <i>Mt2</i> in LacZ-, Numb1-, and Numb2-overexpressing MGE507 cells. *<i>P</i><0.05, **<i>P</i><0.01 compared to LacZ-overexpressing cells. (C) Cell proliferation assay in LacZ-, Numb1-, and Numb2-overexpressing MGE507 cells. **<i>P</i><0.01 compared to LacZ-overexpressing cells. (D) H₂O₂-induced changes in cell viability in LacZ-, Numb1-, and Numb2-overexpressing MGE507 cells. **<i>P</i><0.01 compared to LacZ-overexpressing cells.</p

Expression levels of the m-Numb splicing variants in the stomach.

<p>(A) Schematic representation of the <i>m-Numb</i> gene and the primer designed for m-Numb <i>mRNA</i> amplification. (B) Expression of the PTBS- and PTBL-types of <i>m-Numb mRNA</i> in the stomach of ethanol-administered wild-type (white bars) and Msi1-KO (black bars) mice. Absolute ethanol was administered to both groups of mice and the mRNA expression of each of the splicing variants of <i>m-Numb</i> was analyzed by real-time PCR using SYBR Green. The expression levels were expressed as fold-change relative to the expression in the wild-type animals at 0 h. GAPDH was used as internal standard. (C) Semi-quantitative PCR was performed to confirm the expression of the complete PTBL-type of <i>m-Numb mRNA</i>, which was induced after gastric damage (at 5 h after ethanol administration). The primers used were the PTBL forward primer, and PRRS and PRRL reverse primers. <i>GAPDH</i> was used as the internal standard. The intensity of each band was analyzed, and the results are shown as fold-change relative to the expression in wild-type mice. *<i>P</i><0.05 compared to Msi1-KO mice at 0 h, **<i>P</i><0.01 compared to wild-type mice at 0 h.</p