In-hospital grouping rehabilitation of hybrid closed-wedge high tibial osteotomy results in shorter hospital stays and better clinical outcomes.

[Purpose] This study aimed to examine the impact of physiotherapy on various patients who underwent hybrid closed-wedge high tibial osteotomy. [Participants and Methods] Eighty-four patients were divided into three groups: non-weight-bearing, enhanced recovery after surgery, and grouping exercise. The number of hospital days, distinctions in the duration of cane-walking independence, and postoperative complications were compared among the three groups. Furthermore, the Japanese Orthopaedic Association score and physical function were assessed preoperatively and at 3 and 12 months postoperatively. [Results] There were no considerable differences in postoperative complications among the three groups, and the mean hospital stay was the shortest for the grouping exercise group. At 3 months postoperatively, the grouping exercise group reported less walking pain than the enhanced recovery after surgery group. At 3 and 12 months postoperatively, the grouping exercise group showed greater mean knee extensor strength and a higher mean Japanese Orthopaedic Association score than the non-weight-bearing group. [Conclusion] Grouping exercise therapy, in addition to enhanced recovery after surgery protocol, results in shorter hospital stays, no difference in postoperative complications, and good clinical outcomes.

Association between clinical symptoms and lateral thrust 12 months after high tibial osteotomy.

[Purpose] This study aimed to assess the correlation between lateral thrust and clinical symptoms after high tibial osteotomy and determine lower limb alignments that may decrease lateral thrust. [Participants and Methods] We included 54 patients (73 knees) who underwent high tibial osteotomy. Clinical symptoms, including the Japanese Orthopaedic Association score and the hip-knee-ankle angle measured via radiography, were assessed 12 months postoperatively. Lateral thrust was measured using three-dimensional motion analyses. Logistic regression was used to calculate the cut-off values with good Japanese Orthopaedic Association score and lateral thrust as dependent variables and both lateral thrust and hip-knee-ankle angle as independent variables. [Results] The lateral thrust cut-off was 3.1° (sensitivity: 0.83; specificity: 0.74; area under the curve: 0.76), while that of the hip-knee-ankle angle was 1.9° of valgus (sensitivity: 0.71; specificity: 0.81; area under the curve: 0.72). [Conclusion] Good clinical outcomes after high tibial osteotomy can be expected with a lateral thrust of ≤3.0°, indicating that the target hip-knee-ankle angle should be 2.0° valgus. In cases where valgus alignment is insufficient, lateral thrust may develop, which should be assessed using gait analysis.

Gene expression profiles of multiple brain regions in rats differ between developmental and postpubertal exposure to valproic acid.

We have previously reported that the valproic acid (VPA)-induced disruption pattern of hippocampal adult neurogenesis differs between developmental and 28-day postpubertal exposure. In the present study, we performed brain region-specific global gene expression profiling to compare the profiles of VPA-induced neurotoxicity between developmental and postpubertal exposure. Offspring exposed to VPA at 0, 667, and 2000 parts per million (ppm) via maternal drinking water from gestational day 6 until weaning (postnatal day 21) were examined, along with male rats orally administered VPA at 0, 200, and 900 mg/kg body weight for 28 days starting at 5 weeks old. Four brain regions-the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis-were subjected to expression microarray analysis. Profiled data suggested a region-specific pattern of effects after developmental VPA exposure, and a common pattern of effects among brain regions after postpubertal VPA exposure. Developmental VPA exposure typically led to the altered expression of genes related to nervous system development (Msx1, Xcl1, Foxj1, Prdm16, C3, and Kif11) in the hippocampus, and those related to nervous system development (Neurod1) and gliogenesis (Notch1 and Sox9) in the corpus callosum. Postpubertal VPA exposure led to the altered expression of genes related to neuronal differentiation and projection (Cd47, Cyr61, Dbi, Adamts1, and Btg2) in multiple brain regions. These findings suggested that neurotoxic patterns of VPA might be different between developmental and postpubertal exposure, which was consistent with our previous study. Of note, the hippocampal dentate gyrus might be a sensitive target of developmental neurotoxicants after puberty.

[Evaluation of Skeletal Muscle Mass and Functions during Perioperative Period of Colorectal Cancer Patients].

Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass, loss of muscle strength and/or reduced physical performance. Sarcopenia has repeatedly been reported as a strong predictor of both short- and long-term outcomes following surgical treatment for colorectal cancer. In this study, 86 primary colorectal cancer cases who received surgery at our hospital were examined. To evaluate which factor amongst muscle volume, muscle strength or physical performance would be important to avoid sarcopenia after surgery, we examined objective values of muscle volume, muscle strength and physical performance respectively. We also divided patients into groups by their ages or procedures of surgeries, then compared and analyzed within those groups. The results showed that most patients tended to lose their muscle volume of their legs and their physical performance after their surgeries. We also found patients who were equal or older than 75-year-old and patients who received open surgeries tended to lose their muscle volume or physical performance after their surgeries. These groups of patients have a potential risk to turn sarcopenia after surgeries. It would be important to observe each of 3 factors such as skeletal muscle volume, muscle strength and physical performance to evaluate precisely their condition of sarcopenia. Tailor-made peri-operative rehabilitation programs, especially for elderly patients or patients who received open surgeries, would be a possible solution to avoid sarcopenia after surgery for colorectal cancer.

Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists.

Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.

[Evaluation of Skeletal Muscle Mass and Functions during Perioperative Period of Breast Cancer Patients].

Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass, strength and function. Sarcopenia has repeatedly been reported as a strong predictor of both short- and long-term outcomes following surgical treatment for breast cancer. In this study, 41 primary breast cancer cases who received surgery at our hospital were examined. To evaluate which factor amongst muscle volume, power or function would be most important to avoid sarcopenia after surgery, we examined muscle volume, power and function respectively. We also divided patients into groups by their ages or procedures of surgeries, then compared and analyzed within those groups. The results showed their grip power of the same side of their breast cancer and muscle volume of their legs has been decreased after surgeries. We also found patients who were equal or older than 75 years old and patients who received total mastectomy tended to lose their muscle volume or muscle power after their surgeries. These groups of patients would have potential risk to become sarcopenia after surgeries. It would be important to observe each of 3 factors, skeletal muscle volume, power and function to evaluate precisely their condition of sarcopenia. Tailor-made peri-operative rehabilitation programs, especially for elderly patients or patients who received total mastectomy, would be a possible solution to avoid sarcopenia after surgery for breast cancer.

Mechanical Thrombectomy for Acute Ischemic Stroke Complicated by Bacterial Meningitis and Infective Endocarditis.

Objective: We report a case of cerebral embolism from a bacterial embolus due to infective endocarditis (IE) during treatment of bacterial meningitis. Case Presentation: During treatment of bacterial meningitis, an 82-year-old woman developed left middle cerebral artery embolism. Mechanical thrombectomy was performed, and the yellowish-white emboli were retrieved. From the culture and pathological findings of the embolus, the same bacteria as the meningitis, Streptococcus gordonii, was identified and was considered to originate from IE. She was treated by postoperative antibiotics, but was transferred to the rehabilitation hospital on the 37th postoperative day due to slight right hemiparesis. Conclusion: We should always consider bacterial embolism in acute ischemic stroke combined with bacterial meningitis.

[Assessment for Local Treatment for Elderly Breast Cancer Cases].

The number of elderly breast cancer patients has been increasing recently nevertheless the optimal treatment for the elderly breast cancer patients still remains controversial. In this study, 21 primary breast cancer cases who were equal or older than 85 years old at our hospital were examined their clinical and pathological features. These 21 cases were divided into 2 group; Group A; ten cases who received operations, Group B; eleven cases who did not receive operations. T categories, M categories and clinical stages in Group B were significantly higher than those of Group A. The main causing reason why Group B cases had not received operations was that their primary breast cancer were too advanced to perform operation. Instead of operation, most Group B cases received endocrine therapy or radiotherapy. Group A cases received standard operative procedures including partial or total mastectomy and biopsies or dissection of axillary lymph nodes. Besides, their post- operative courses were good and safe. These results suggest that even for elderly patients, early diagnosis and treatment could improve their prognosis and quality of life. In addition, careful surveillances for elderly breast cancer patients, those who tend to stop attending regular check up to their hospital, should be considered for further assessment for characteristics of elderly breast cancer patients.

Lack of preventive effect of maternal exposure to α-glycosyl isoquercitrin and α-lipoic acid on developmental hypothyroidism-induced aberrations of hippocampal neurogenesis in rat offspring.

Hypothyroidism during the developmental stage induces disruption of hippocampal neurogenesis in later life, as well as inducing oxidative stress in the brain. The present study investigated the preventive effect of co-exposure to an antioxidant on disruptive neurogenesis induced by developmental exposure to anti-thyroid agent in rats. For this purpose, we used two antioxidants, α-glycosyl isoquercitrin (AGIQ) and α-lipoic acid (ALA). Mated female Sprague Dawley rats were either untreated (control) or treated with 12 ppm 6-propyl-2-thiouracil (PTU), an anti-thyroid agent, in drinking water from gestational day 6 to postnatal day (PND) 21, the latter group being subjected to feeding basal diet alone or diet containing AGIQ at 5,000 ppm or ALA at 2,000 ppm during PTU exposure. On PND 21, PTU-exposed offspring showed reductions in a broad range of granule cell lineage subpopulations and a change in the number of GABAergic interneuron subpopulations. Co-exposure of AGIQ or ALA with PTU altered the transcript levels of many genes across multiple functions, suggestive of enhancement of synaptic plasticity and neurogenesis. Nevertheless, immunohistochemical results did not support these changes. PTU exposure and co-exposure of AGIQ or ALA with PTU did not alter the hippocampal lipid peroxidation level. The obtained results suggest a possibility that thyroid hormone depletion itself primarily disrupts neurogenesis and that oxidative stress may not be involved in the disruption during development. Transcript expression changes of many genes caused by antioxidants may be the result of neuroprotective actions of antioxidants rather than their antioxidant activity. However, no preventive effect on neurogenesis suggested impairment of protein synthesis via an effect on mRNA translation due to hypothyroidism.

Postoperative Cerebellar Cyst with Pseudomeningocele After Tumor Removal at the Craniovertebral Junction.

BACKGROUND: Cerebellar cyst formation after surgery is uncommon, and few cases of this condition have been previously reported. These cases had an intraparenchymal cyst in the cerebellar hemisphere that required surgical fenestration of the cyst. We herein present a rare case of a postoperative cerebellar cyst with pseudomeningocele and magnetic resonance images indicating a fistula between the cyst and pseudomeningocele. CASE DESCRIPTION: A patient presented with an intraparenchymal cyst and surrounding edema in the cerebellar hemisphere that developed after a C1 laminectomy and a small suboccipital craniectomy for the removal of an accessory nerve neurinoma at the craniovertebral junction. Fast imaging employing steady-state acquisition images identified the fistula connecting the cyst and extradural cerebrospinal fluid retention. Conservative management with administration of dexamethasone induced spontaneous regression of the cyst, and no recurrence had occurred by the 1-year follow-up. CONCLUSIONS: Watertight dural closure is important for the prevention of this rare complication after posterior fossa surgery. However, an arachnoid tear on the cerebellar fissure and adjacent dural defect are necessary antecedents for this rare condition. High-resolution fast imaging employing steady-state acquisition images could provide additional information for the etiology of postoperative cerebellar cyst.

Clinical and pathological characteristics of acute myelogenous leukemia in a female koala with diabetes mellitus.

A female koala presented with hyperglycemia related to diabetes mellitus diagnosed at 9 years and treated with insulin. She presented with nasal hemorrhage, anemia, leukocytosis, and tachypnea at 10 years. A blood smear examination revealed scattered, atypical large myeloid cells and a clinical diagnosis of myelogenous leukemia was made. White blood cell count reached a maximum of 295 × 102/µl, with evidence of severe regenerative anemia and thrombocytopenia. Grossly, systemic lymph node enlargement, fragile liver with hemorrhage, and bloody ascites were observed. Histopathologically, atypical myeloid cells, including myelocytic and metamyelocytic cells, were scattered in the vasculature and surrounding tissues throughout the organs. The patient was infected with a koala retrovirus, which might have caused the myelogenous leukemia.

Twenty-eight-day repeated oral doses of sodium valproic acid increases neural stem cells and suppresses differentiation of granule cell lineages in adult hippocampal neurogenesis of postpubertal rats.

Developmental exposure to valproic acid (VPA), a model compound for experimental autism, has shown to primarily target GABAergic interneuron subpopulations in hippocampal neurogenesis of rat offspring. The VPA-exposed animals had revealed late effects on granule cell lineages, involving progenitor cell proliferation and synaptic plasticity. To investigate the possibility whether hippocampal neurogenesis in postpubertal rats in a protocol of 28-day repeated exposure is affected in relation with the property of a developmental neurotoxicant by developmental exposure, VPA was orally administered to 5-week-old male rats at 0, 200, 800 and 900 mg/kg body weight/day for 28 days. At 900 mg/kg, GFAP+ cells increased in number, but DCX+ cells decreased in number in the granule cell lineages. Moreover, CHRNB2+ cells and NeuN+ postmitotic neurons decreased in number in the hilus of the dentate gyrus. Transcript level examined at 900 mg/kg in the dentate gyrus was increased with Kit, but decreased with Dpsyl3, Btg2, Pvalb and Chrnb2. These results suggest that VPA increased type-1 stem cells in relation to the activation of SCF-KIT signaling and suppression of BTG2-mediated antiproliferative effect on stem cells. VPA also decreased type-3 progenitor cells and immature granule cells probably in relation with PVALB+ interneuron hypofunction and reduced CHRNB2+ interneuron subpopulation in the hilus, as well as with suppression of BTG2-mediated terminal differentiation of progenitor cells. Thus, the disruption pattern of VPA by postpubertal exposure was different from developmental exposure. However, disruption itself can be detected, suggesting availability of hippocampal neurogenesis in detecting developmental neurotoxicants in a 28-day toxicity study.

[Assessment of Prognosis after Surgical Treatment for Colorectal Liver Metastasis Using a Nomogram].

A nomogram is a statistical tool that can provide the specific outcomes of individual patients. In this study, we used a nomogram developed by Beppu et al to evaluate the prognoses of 38 patients who underwent hepaticresec tion at our hospital. This nomogram predicts disease-free survival(DFS)after hepatic resection for colorectal liver metastasis based on 6 clinical and oncological factors. Using this nomogram, we divided the 38 patients into 3 groups: Group N, actual DFS was almost similar to the estimated median DFS(EMDFS)provided by the nomogram; Group A, DFS was longer than EMDFS; and Group B, DFS was shorter than EMDFS. Then, we compared and analyzed clinical and oncological factors between Groups A and B. Group B patients tended to have single metastasis and non-normal levels of CA19-9. Besides, Group B patients had DFS shorter than approximately 2 years. These results suggest that if CA19-9 levels are not normalized after hepaticresec tion for single metastasis, we should consider careful observation and adjuvant chemotherapy for potential micrometastasis.

Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene.

Maternal hexachlorophene (HCP) exposure causes transient disruption of hippocampal neurogenesis in mouse offspring. We examined epigenetically hypermethylated and downregulated genes related to this HCP-induced disrupted neurogenesis. Mated female mice were dietary exposed to 0 or 100 ppm HCP from gestational day 6 to postnatal day (PND) 21 on weaning. The hippocampal dentate gyrus of male offspring was subjected to methyl-capture sequencing and real-time reverse transcription-polymerase chain reaction analyses on PND 21. Validation analyses on methylation identified three genes, Dlx4, Dmrt1, and Plcb4, showing promoter-region hypermethylation. Immunohistochemically, DLX4+, DMRT1+, and PLCB4+ cells in the dentate hilus co-expressed GAD67, a γ-aminobutyric acid (GABA)ergic neuron marker. HCP decreased all of three subpopulations as well as GAD67+ cells on PND 21. PLCB4+ cells also co-expressed the metabotropic glutamate receptor, GRM1. HCP also decreased transcript level of synaptic plasticity-related genes in the dentate gyrus and immunoreactive granule cells for synaptic plasticity-related ARC. On PND 77, all immunohistochemical cellular density changes were reversed, whereas the transcript expression of the synaptic plasticity-related genes fluctuated. Thus, HCP-exposed offspring transiently reduced the number of GABAergic interneurons. Among them, subpopulations expressing DLX4, DMRT1, or PLCB4 were transiently reduced in number through an epigenetic mechanism. Considering the role of the Dlx gene family in GABAergic interneuron migration and differentiation, the decreased number of DLX4+ cells may be responsible for reducing those GABAergic interneurons regulating neurogenesis. The effect on granule cell synaptic plasticity was sustained until the adult stage, and reduced GABAergic interneurons active in GRM1-PLCB4 signaling may be responsible for the suppression on weaning.

Downregulation of UBE2E2 in rat liver cells after hepatocarcinogen treatment facilitates cell proliferation and slowing down of DNA damage response in GST-P-expressing preneoplastic lesions.

We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P+ foci, compared with GST-P+ foci expressing UBE2E2. However, p21WAF1/CIP1, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA+ cells and γH2AX+ cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P+ foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P+ foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90days. Hepatocarcinogen treatment for 28 or 90days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA+ or γH2AX+ cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P+ proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis.

Downregulation of TMEM70 in Rat Liver Cells After Hepatocarcinogen Treatment Related to the Warburg Effect in Hepatocarcinogenesis Producing GST-P-Expressing Proliferative Lesions.

We previously observed downregulation of mitochondrial oxidative phosphorylation-related protein, TMEM70, which is suggestive of disrupted cellular senescence, in GST-P-expressing (+) proliferative lesions from early hepatocarcinogenesis stages in rats. The present study investigated the immunohistochemical relationship between TMEM70 downregulation and cellular metabolic changes in carcinogenic processes, as well as the onset of the liver cell respiratory changes after repeated hepatocarcinogen treatment in rats. At the early hepatocarcinogenesis stage in a 2-stage model, GST-P+ preneoplastic lesions showing TMEM70 downregulation also downregulated the mitochondrial ATPase, ATPB, but upregulated glycolysis-related glucose transporter member 1 (GLUT1) and glucose-6-phosphate dehydrogenase, suggesting a metabolic shift from oxidative phosphorylation to glycolysis, known as the Warburg effect. Combined downregulation of TMEM70 and ATPB increased proliferation activity in GST-P+ preneoplastic lesions, suggesting cell proliferation facilitation by reducing mitochondrial respiration. Concurrent GLUT1-upregulation and TMEM70-downregulation increased nuclear phosphorylated c-MYC+ cells in GST-P+ preneoplastic lesions, suggesting c-MYC-mediated transcription facilitation to promote glycolysis and cell proliferation. The TMEM70-related metabolic shift was enhanced in GST-P+ neoplastic lesions, suggesting a contribution to tumor progression. Conversely, the TMEM70-related metabolic shift was lacking in peroxisome proliferator-activated receptor-α agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs. Transcript expression analysis following 28- and 90-day repeated hepatocarcinogen treatment showed downregulation of Tmem70 from day 28 and upregulation of Pkm and Myc at day 90, suggesting early onset of a catastrophic cellular senescence-related metabolic shift beginning from depressed mitochondrial respiration in the liver. These results suggest a contribution of TMEM70 downregulation to the Warburg effect, which directs tumor promotion and progression in GST-P+-linked hepatocarcinogenesis in rats.

Differential effects between developmental and postpubertal exposure to N-methyl-N-nitrosourea on progenitor cell proliferation of rat hippocampal neurogenesis in relation to COX2 expression in granule cells.

This study was performed to compare the exposure effects of N-methyl-N-nitrosourea (MNU), a cytocidal agent of proliferating cells, on rat hippocampal neurogenesis between developmental and postpubertal periods. Developmental exposure through maternal drinking water from gestational day 6 to day 21 after delivery on weaning decreased GFAP-immunoreactive (+) stem cells and increased immunoreactive cells indicative of subsequent progenitor and postmitotic immature neuronal populations, TUNEL+ or p21Cip1/Waf1+ stem/progenitor cells and COX2+ granule cells, on postnatal day (PND) 21. On PND 77 after cessation of developmental exposure, NeuN+ postmitotic granule cells decreased in number. Postpubertal exposure by oral gavage for 28days decreased the numbers of all granule cell lineage populations and ARC+ or COX2+ granule cells and increased the number of TUNEL+ stem/progenitor cells. These results suggested that both developmental and postpubertal exposure caused apoptosis of stem/progenitor cells. However, developmental exposure increased COX2 expression to facilitate intermediate progenitor cell proliferation and increased neuronal plasticity. This effect was concurrent with the induction of p21Cip1/Waf1 that causes cell cycle arrest of stem/progenitor cells in response to accumulating DNA damage on weaning, resulting in a subsequent reduction of postmitotic granule cells. In contrast, postpubertal exposure suppressed neuronal plasticity as evidenced by downregulation of ARC and COX2. The COX2 downregulation was responsible for the lack of facilitating stem/progenitor cell proliferation. Induction of apoptosis and the lack of cell proliferation facilitation may be responsible for the overall reduction of neurogenesis caused by postpubertal exposure. Thus, the disrupted pattern of hippocampal neurogenesis induced by MNU is different between developmental and postpubertal exposure.

Late effect of developmental exposure to glycidol on hippocampal neurogenesis in mice: Loss of parvalbumin-expressing interneurons.

Developmental exposure to glycidol of rats causes axonal injury targeting axon terminals in dams and transient disruption of late-stage differentiation of hippocampal neurogenesis, accompanying sustained increase in the number of reelin-producing or calretinin-expressing interneurons in offspring. The molecular mechanism of disruptive neurogenesis probably targets the newly generating nerve terminals. We previously found differences between mice and rats in the effects on hippocampal neurogenesis after developmental exposure to the same neurotoxic substances. In the present study, we examined the effects and underlying mechanisms of developmental exposure to glycidol on hippocampal neurogenesis in mice. Glycidol (800 or 1600ppm) was administered in drinking water to mated female mice from gestational day 6 to postnatal day 21. Compared to mice drinking water without glycidol (control), the exposed dams showed axon terminal injury at both concentrations of glycidol. The offspring of the dams that had received 1600ppm glycidol had fewer parvalbumin (PVALB)+ γ-aminobutyric acid (GABA)-ergic interneurons and neuron-specific nuclear protein+ postmitotic neurons in the hilus of the hippocampal dentate gyrus. Thus, exposure of glycidol to adult mice induced axonal degeneration equivalent to that seen in the rat; however, the target mechanism for the disruption of hippocampal neurogenesis by developmental exposure was different from that in rats, with the hilar neuronal population not affected until adulthood. Considering the role of PVALB+ GABAergic interneurons in the brain, developmental glycidol exposure in mice may cause a decline in cognitive function in later life, and involve a different mechanism from that targeting axon terminals in rats.

Late Effect of Developmental Exposure to 3,3'-Iminodipropionitrile on Neurogenesis in the Hippocampal Dentate Gyrus of Mice.

The effects of developmental exposure to 3,3'-iminodipropionitrile (IDPN), a neurotoxicant that causes proximal axonopathy, on mouse hippocampal neurogenesis was examined. Pregnant mice were exposed to IDPN at 0, 600, or 1200 ppm in their drinking water from gestational day 6 to postnatal day (PND) 21. On PND 21, male offspring showed increased postmitotic neuron-specific NeuN-immunoreactive(+) granule cell numbers in the dentate subgranular zone (SGZ) and granule cell layer (GCL) and decreased glutamate receptor gene Grin2d levels in the dentate gyrus at 1200 ppm. On PND 77, decreased numbers were observed for TBR2+ progenitor cells in the SGZ at ≥600 ppm and GFAP+ stem cells, DCX+ progenitor cells and immature granule cells, NeuN+ immature and mature granule cells, PCNA+ proliferating cells in the SGZ and/or GCL, and immunoreactive cells for ARC or FOS, immediate-early gene products related to neuronal and synaptic plasticity, in the GCL at 1200 ppm. Additionally, at 1200 ppm of IDPN, downregulation of Kit, the gene encoding the stem cell factor (SCF) receptor, and upregulation of Kitl, encoding SCF, were observed in the dentate gyrus. Therefore, maternal IDPN exposure in mice affects neurogenesis involving glutamatergic signals at the end of developmental exposure, with late effects suppressing SGZ cell proliferation, reducing the broad range of granule cell lineage population, which may be responsible for SCF receptor downregulation. The upregulated SCF was likely a feedback response to the decreased receptor level. These results suggest that reduced SCF signaling may cause suppressed neuronal and synaptic plasticity.