Biomedical subjects

Grace S Lee

Publications and source records attributed to Grace S Lee.

7 recordsLinked to original sources

PubMed2006

Interactive effects of cadmium and all-trans-retinoic acid on the induction of forelimb ectrodactyly in C57BL/6 mice.

BACKGROUND: Most toxicological studies have tested single chemical agents at relatively high doses, and fewer studies have addressed the toxic effects of chemical interactions. It is important to understand the toxicity of chemical mixtures in order to assess the more realistic risks of environmental and occupational exposures. A number of chemicals are known to induce a predominantly postaxial forelimb ectrodactyly in C57BL/6 mice, including acetazolamide, ethanol, cadmium, valproic acid, carbon dioxide, dimethadione, phenytoin, and 13-cis-retinoic acid and all-trans-retinoic acid (RA). In the present study, the interactive effects of coadministration of cadmium and RA on developing limbs were investigated. METHODS: Pregnant C57BL/6 mice were treated with different intraperitoneal (IP) doses of cadmium chloride (CdCl2) and/or RA on gestational day (GD) 9.5, and fetuses were collected on GD 18 and double stained for examination of skeletal defects. RESULTS: When RA was given simultaneously with cadmium, a significant increase in the incidence and severity of forelimb ectrodactyly (predominantly postaxial) was observed compared to the results with corresponding doses of cadmium or RA alone. When mice were exposed to subthreshold doses of both cadmium (0.5 mg/kg) and RA (1 mg/kg), the combined treatment exceeded the threshold, resulting in forelimb ectrodactyly in 19% of the fetuses. Moreover, coadministration of cadmium and RA at doses exceeding the respective thresholds showed a synergistic effect, that is, 92% of fetuses were found with the forelimb defect as opposed to 10% if the response were additive. CONCLUSIONS: The findings demonstrate that concurrent exposure to these teratogens can have a synergistic effect and that subteratogenic doses may combine to exceed a threshold.

Animals↗

PubMed2005

A gene(s) for all-trans-retinoic acid-induced forelimb defects mapped and confirmed to murine chromosome 11.

All-trans-retinoic acid (RA) induces various anatomical limb dysmorphologies in mice dependent on the time of exposure. During early limb development, RA induces forelimb ectrodactyly (digital absence) with varying susceptibilities for different inbred mouse strains; C57BL/6N are highly susceptible while SWV are resistant. To isolate the genetic basis of this defect, a full-genome scan was performed in 406 backcross fetuses of F(1) males to C57BL/6N females. Fetuses were exposed via a maternal injection of 75 mg of RA per kilogram of body weight on gestational day 9.25. The genome-wide analysis revealed significant linkage to a chromosome 11 locus near D11Mit39 with a maximum LOD score of 9.0 and to a chromosome 4 locus near D4Mit170. An epistatic interaction was detected between loci on chromosome 11 (D11Mit39) and chromosome 18 (D18Mit64). Linkage to the chromosome 11 locus (D11Mit39) was confirmed in RA-treated backcross fetuses of F(1) females to C57BL/6N males. Loci associated with bone density/mass in both human and mouse were previously detected in the same region, suggesting a mechanistic linkage with bone homeostasis. The human syntenic region of this locus has been previously linked to Meckel syndrome; the phenotype includes postaxial polydactyly, an ectopic digital defect hypothesized to be induced by a common molecular pathway with ectrodactyly.

Animals↗

PubMed2004

Differences between smokers and nonsmokers in regional gray matter volumes and densities.

BACKGROUND: Magnetic resonance imaging (MRI) studies have demonstrated large-scale brain abnormalities in cigarette smokers, such as ventricular enlargement and atrophy. Converging lines of evidence point to functional differences between smokers and nonsmokers in specific brain regions, namely the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. Using MRI, we examined these regions for differences in gray matter between smokers and nonsmokers. METHODS: Thirty-six otherwise healthy adults (19 smokers and 17 nonsmoking control subjects) underwent three-dimensional Fourier-transform spoiled-gradient-recalled acquisition MRI of the brain. Both hand-drawn regions of interest and the computer program voxel-based morphometry were used to assess group differences in regional gray matter volumes and densities, respectively. RESULTS: Smokers had smaller gray matter volumes and lower gray matter densities than nonsmokers in the PFC bilaterally, along with smaller volumes in the left dorsal ACC and lower gray matter densities in the right cerebellum. Smokers also had negative associations between pack-year smoking history and PFC gray matter densities. CONCLUSIONS: Smokers and nonsmokers differed in regional gray matter in brain areas previously linked with nicotine dependence. These findings might reflect effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors.

Adult↗

PubMed2004

Smoking-induced ventral striatum dopamine release.

OBJECTIVE: Substantial evidence from animal models demonstrates that dopamine release in the ventral striatum underlies the reinforcing properties of nicotine. The authors used [(11)C]raclopride bolus-plus-continuous-infusion positron emission tomography (PET) to determine smoking-induced ventral striatum dopamine release in humans. METHOD: Twenty nicotine-dependent smokers (who smoked > or =15 cigarettes/day) underwent a [(11)C]raclopride bolus-plus-continuous-infusion PET session. During the session, subjects had a 10-minute break outside the PET apparatus during which 10 subjects smoked a cigarette and 10 did not smoke (as a control condition). RESULTS: The group that smoked had greater reductions in [(11)C]raclopride binding potential in ventral striatum regions of interest than the group that did not smoke, particularly in the left ventral caudate/nucleus accumbens and left ventral putamen (range for smoking group=-25.9% to -36.6% reduction). Significant correlations were found between change from before to after the smoking break in craving ratings and change from before to after the break in binding potential for these two regions. CONCLUSIONS: Nicotine-dependent subjects who smoked during a break in PET scanning had greater reductions in [(11)C]raclopride binding potential (an indirect measure of dopamine release) than nicotine-dependent subjects who did not smoke. The magnitude of binding potential changes was comparable to that found in studies that used similar methods to examine the effects of other addictive drugs.

Adult↗

PubMed2004

Retinoid-induced limb malformations.

The developing limb has been studied extensively and is a useful model to study morphogenesis. During embryogenesis, limb formation is initiated as a budding off from the embryonic lateral body wall. Limb pattern is specified by a series of epithelial-mesenchymal interactions, directing proximodistal, dorsoventral and anteroposterior axes. Vitamin A metabolites, especially retinoic acid, are known to play an important role in limb development, and the effects of retinoic acid may be mediated through the retinoid receptor signaling pathways. Accumulated evidence has shown that inadequate levels (excess or deficiency) of retinoic acid cause a wide range of limb malformations. Some species have the capacity to regenerate amputated limbs, and retinoids certainly affect this process, but there is debate regarding the extent that regeneration recapitulates development. In this review, phenotypic features, pathogenesis and the molecular basis of retinoid-induced limb malformations are discussed with a description of normal limb development and endogenous retinoid pathways.

Animals↗

PubMed2003

Effect of arsenite, maternal age, and embryonic sex on spina bifida, exencephaly, and resorption rates in the splotch mouse.

BACKGROUND: This study examines interactions of a mutation in Pax3, embryonic sex, advanced maternal age, and arsenite exposure in the splotch (Sp) mouse model, with the aim of describing gene-environment interactions for neural tube defects and embryonic lethality. METHODS: Splotch heterozygous C57BL/6J mice were crossed to produce offspring of three genotypes with a common maternal genotype that were exposed to either sodium arsenite on gestational day (GD) 8.0, or advanced maternal age (dams older than 12 months). Embryos were extracted on GD 12 and genotyped for both Pax3 and sex. RESULTS: Arsenite treatment was a significant contributor to both exencephaly and spina bifida. Advanced maternal age resulted in a high exencephaly rate in Sp/Sp female embryos (but not other genotypes) and a high overall resorption rate. Arsenite treatment and advanced maternal age resulted in elevated sex ratios (male:female) for heterozygous and wild-type embryos. The sex ratio was highest for wild-type embryos and was lowered as the number of mutant Pax3 alleles increased. The sex ratio was not significantly different from 1.0 for splotch homozygotes. Control litters had spina bifida rates that were 95% in homozygous, 6% in heterozygous, and 0% in wild-type embryos. CONCLUSIONS: If arsenite produces exencephaly by inactivating the Pax3 protein, then the fact that the exencephaly rate was increased in Sp/Sp embryos with no functional Pax3 indicates that arsenite may either induce this defect through additional pathways, or may alter the response via modifier genes. Genetic and environmental factors contributed to the determination of murine sex ratios, with female embryos being more susceptible to loss.

Abnormalities, Drug-Induced↗

PubMed2002

Brain metabolic changes during cigarette craving.

BACKGROUND: In functional brain imaging studies, exposure to cues related to cocaine, opiates, and alcohol in dependent individuals is associated with activation of the anterior cingulate gyrus, amygdala, orbitofrontal cortex, and dorsolateral prefrontal cortex. Craving for these substances positively correlates with activity in the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior insula. The objective of this study was to determine changes in regional cerebral glucose metabolism and correlations between craving and regional metabolism in heavy cigarette smokers exposed to cigarette-related cues. METHODS: Twenty heavy smokers (who smoked > or =20 cigarettes per day) and 20 nonsmoking control subjects underwent 2 fluorine 18-fluorodeoxyglucose positron emission tomography scans 10 days apart in randomized order: one while watching a videotape that presented cigarette-related cues and handling a cigarette, and the other while watching an educational (nature) videotape and handling a neutral object (pen). RESULTS: From the neutral to the cigarette cue scan, heavy smokers had greater increases than nonsmoking controls in relative glucose metabolism in the perigenual anterior cingulate gyrus spanning the midline. Significant positive correlations were found between intensity of craving and metabolism in the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior insula bilaterally. An unexpected positive association was found between craving and metabolism in the right sensorimotor cortex. CONCLUSIONS: Brain regions associated with arousal, compulsive repetitive behaviors, sensory integration, and episodic memory are activated during exposure to cigarette-related cues and cigarette craving. These regional brain activations and associations with craving are similar to findings with other addictive substances.

Adult↗