Estimation of benchmark dose for renal dysfunction in a cadmium non-polluted area in Japan

Previously, the association between urinary cadmium (Cd) concentration and indicators of renal dysfunction, including beta(2)-microglobulin (beta(2)-MG), total protein and N-acetyl-beta-D-glucosaminidase (NAG) were investigated in 1270 inhabitants > or = 50 years of age (547 men, 723 women) in a Cd non-polluted area in Japan and showed that a dose-response relationship existed between renal effects and Cd exposure in the general environment without any known Cd pollution. However, the threshold levels of urinary Cd could not be estimated at that time. In the present study, the threshold levels of urinary Cd were estimated as the benchmark dose low (BMDL) using the benchmark dose (BMD) approach. Urinary Cd excretion was divided into 6-7 categories, and an abnormality rate was calculated for each. Cut-off values for urinary substances were defined as corresponding to the 84% upper limit values, which were calculated from 2034 persons who had been living in the non-polluted areas and did not smoke. Then the BMD and BMDL were calculated using a log-logistic model. The values of BMD and BMDL for all urinary substances could be calculated. The BMDL for the 84% cut-off value of beta(2)-MG, setting an abnormal value at 5%, was 2.0 microg g(-1) creatinine (cr) in men and 1.6 microg g(-1) cr in women. In conclusion, the present study demonstrated that the threshold level of urinary Cd could be estimated in people living in the general environment without any known Cd-pollution in Japan, and the value was inferred to be almost the same as that in Belgium and Sweden.     

Tolerable Level of Lifetime Cadmium Intake Estimated as a Benchmark Dose Low, Based on Excretion of ;2-Microglobulin in the Cadmium-Polluted Regions of the Kakehashi River Basin, Japan

No abstract available.     

Expression of the cadherin-11 gene is a discriminative factor between articular and growth plate chondrocytes

OBJECTIVE: Calcification of hypertrophic chondrocytes is the final step in the differentiation of growth plates, although the precise mechanism is not known. We have established two growth plate-derived chondrocyte cell lines, MMR14 and MMR17, from p53-/- mice (Nakamata T, Aoyama T, Okamoto T, Hosaka T, Nishijo K, Nakayama T, et al. In vitro demonstration of cell-to-cell interaction in growth plate cartilage using chondrocytes established from p53-/- mice. J Bone Miner Res 2003;18:97-107). Prolonged in vitro culture produced calcified nodules in MMR14, but not in MMR17. Factors responsible for the difference in calcification between the two cell lines may also be involved in the physiological calcification in growth plate. DESIGN: Gene expression profiles of MMR14 and MMR17 were compared using a cDNA microarray to identify candidate genes involved in the calcification process. RESULTS: Forty-five genes were identified as upregulated in MMR14, including the cadherin-11 (Cdh-11) gene. The expression of Cdh-11 in MMR14 was detected in cell-cell junctions, while no expression was observed in MMR17. Primary cultured chondrocytes from growth plate (GC) also expressed the Cdh-11, and the staining of Cdh-11 was observed in the late hypertrophic zone of growth plate. Cell aggregation assays showed that chondrocytes required Ca2+ to form nodules, and knockdown of the Cdh-11 gene expression using short interfering RNA inhibited the formation of calcified nodules in MMR14. The introduction of Cdh-11 into MMR17 failed to produce calcified nodules indicating that Cdh-11 is one, but not the sole, factor responsible for the production of calcified nodules. CONCLUSION: Although the physiological role is still unclear, Cdh-11 is a discriminative factor between articular and growth plate chondrocytes.     

Effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal brain growth and motor and behavioral development in offspring rats

The effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during pregnancy on fetal brain growth and neurobehavioral development in early developmental stages were investigated using rat offspring. TCDD in corn-oil (0.1microg/kg) was orally administrated to the dams from the 9th to 19th gestational day. When TCDD effects on the fetal brain weight were analyzed on the 19th gestational day, weight ratio of the brain to the whole body, and that of the forebrain without the cerebral cortex to the whole brain were larger in the exposed group than those of the control group, suggesting premature fetal brain development. TCDD effects on motor functions were investigated using newborns in an inclined plane task. Motor development assessed by righting response on an inclination was delayed in the exposed offspring in the 8th-12th postnatal day, especially in male. Also, TCDD effects on active avoidance behavior in a shuttle box were investigated using the offspring after weaning. Latency in the active avoidance learning was longer, and locomotor activity was reduced in the exposed male offspring in the 41st-44th postnatal day. The results demonstrated that maternal TCDD exposure delayed fetal brain growth and neurodevelopment of the offspring in early stage, especially in male rats.     

Glycine enhances glutamate-induced excitation in ventromedial hypothalamic neurons in awake rats

The finding that glycine potentiates N-methyl-D-aspartate (NMDA) receptor-mediated responses, has tremendously changed our understanding of glutamatergic synaptic transmission in the brain. Although the phenomenon has been confirmed in number of preparations, it is yet to be demonstrated in awake animals. Further, the controversy that glycine binding sites of NMDA receptor are saturated in vivo or not, can be best verified in awake animals. Here, we have demonstrated that glycine enhanced glutamate-induced neuronal discharges in the ventromedial nucleus of the hypothalamus of awake behaving rats using microiontophoresis technique, suggesting that the glycine binding sites of NMDA receptor are not saturated under physiological conditions.     

Neuronal responses to a delayed-response delayed-reward go/nogo task in the monkey posterior insular cortex

Anatomical connections of the insular cortex suggest its involvement in cognition, emotion, memory, and behavioral manifestation. However, there have been few neurophysiological studies on the insular cortex in primates, in relation to such higher cognitive functions. In the present study, neural activity was recorded from the monkey insular cortex during performance of a delayed-response delayed-reward go/nogo task. In this task, visual stimuli indicating go or nogo responses associated with reward (reward trials) and with no reward (no-reward trials) were presented after eye fixation. In the reward trials, the monkey was required to release a button during presentation of the 2nd visual stimuli after a delay period (delay 1). Then, a juice reward was delivered after another delay (delay 2). The results indicated that the neurons responding in each epoch of the task were topographically localized within the insular cortex, consistent with the previous anatomical studies indicating topographical distributions of afferent inputs from other subcortical and cortical sensory areas. Furthermore, some insular neurons 1) nonspecifically responded to the visual cues and during fixation; 2) responded to the visual cues predicting reward and during the delay period before reward delivery; 3) responded differentially in go/nogo trials during the delay 2; and 4) responded around button manipulation. The observed patterns of insular-neuron responses and the correspondence of their topographical localization to those in previous anatomical studies suggest that the insular cortex is involved in attention- and reward-related functions and might monitor and integrate activities of other brain regions during cognition and behavioral manifestation.     

Aberrant hippocampal spine morphology and impaired memory formation in neuronal platelet-derived growth factor beta-receptor lacking mice

The physiological role of platelet-derived growth factor (PDGF) in the central nervous system (CNS) synaptic function remains uncharacterized. Here we identify physiological roles of PDGF receptor-β (PDGFR-β) in the CNS by conditional knockout of the gene encoding it. In the hippocampus, PDGFR-β colocalized immunohistochemically with both presynaptic synaptophysin and postsynaptic density-95 (PSD-95). In the hippocampal CA1 region, expression levels of postsynaptic proteins, including spinophilin, drebrin, and PSD-95, were significantly decreased in PDGFR-β knockout mice, although presynaptic synaptophysin levels remained comparable to controls. Interestingly, in hippocampal CA1 pyramidal neurons, dendritic spine density in PDGFR-β knockout mice was significantly decreased compared with that seen in wild-type mice, although spine length and number of dendritic branches remained unchanged. Consistent with these findings, impairment in hippocampal long-term potentiation (LTP) and in hippocampus-dependent memory formation were seen in PDGFR-β knockout mice. These results suggest PDGFR-β plays critical roles in spine morphology and memory formation in mouse brain.     

Neuronal responses in the nucleus accumbens shell during sexual behavior in male rats

Previous behavioral studies have indicated that the nucleus accumbens (NAc) shell of a male rat is involved in its sexual behavior; however, no previous studies have investigated neuronal activities in the male rat NAc shell during sexual behavior. To investigate this issue, we recorded single unit activities in the NAc shell of male rats during sexual behavior. Of 123 NAc shell neurons studied, 53, 47, and 40 neurons exhibited significantly changed firing rates at various times during intromission, genital auto-grooming, and sniffing of females, respectively. The two types of NAc shell neurons [putative fast spiking interneurons (pFSIs) and medium spiny neurons (pMSNs)] responded differently during sexual behavior. First, more pFSIs than pMSNs exhibited inhibitory responses to thrusting with intromission and genital grooming, while pFSIs and pMSNs responded similarly to sniffing of females. Second, both pFSIs and pMSNs responded differently to thrusting with and without intromission. Furthermore, NAc shell neuronal activity was significantly different across the different phases of sexual behavior, and the number of NAc shell neurons with delta oscillation, which is related to behavioral inhibition, and high gamma oscillation, which is related to reward perception, increased after ejaculation. Together, our results suggest that the NAc shell is deeply involved in sexual behavior, and changes in NAc shell neuronal activity are related to performance of sexual behavior, encoding cues or contexts related to sexual behavior, reward-related processing, and the inhibition of sexual behavior after ejaculation.     

Hippocampal neuronal responses during signaled licking of gustatory stimuli in different contexts

Neuroanatomical studies suggest that hippocampal formation (HF) receives information from all sensory modalities including taste via the parahippocampal cortices. To date, however, no neurophysiological study has reported that HF neurons encode taste information. In the present study, we recorded CA1 HF neurons from freely behaving rats during performance of a visually‐guided licking task in two different triangular chambers. When a cue lamp came on, the rats were required to press a bar to trigger a tube to protrude into the chambers for 3 s. During this period, the rats could lick one of six sapid solutions: [0.1M NaCl (salty), 0.3M sucrose (sweet), 0.01M citric acid (sour), 0.0001M quinine HCl (bitter), 0.01M monosodium L ‐glutamate (MSG, umami), and a mixture of MSG and 0.001M disodium‐5′‐inosinate (IMP) (MSG+IMP)], and distilled water. Of a total 285 pyramidal and interneurons, the activity of 173 was correlated with at least one of the events in the task—illumination of cue lamps, bar pressing, or licking the solution. Of these, 137 neurons responded during licking, and responses of 62 of these cells were greater to sapid solutions than to water (taste neurons). Multivariate analyses of the taste neurons suggested that, in the HF, taste quality might be encoded based on hedonic value. Furthermore, the activity of most taste neurons was chamber‐specific. These results implicate the HF in guiding appetitive behaviors such as conditioned place preference. © 2010 Wiley‐Liss, Inc.