Biomedical subjects

D Chen

Publications and source records attributed to D Chen.

At least 217 records · Page 12Linked to original sources

PubMed2000

Induction of oxidative DNA damage in the peri-infarct region after permanent focal cerebral ischemia.

To address the role of oxidative DNA damage in focal cerebral ischemia lacking reperfusion, we investigated DNA base and strand damage in a rat model of permanent middle cerebral artery occlusion (MCAO). Contents of 8-hydroxyl-2'-deoxyguanosine (8-OHdG) and apurinic/apyrimidinic abasic sites (AP sites), hallmarks of oxidative DNA damage, were quantitatively measured in nuclear DNA extracts from brains obtained 4-72 h after MCAO. DNA single- and double-strand breaks were detected on coronal brain sections using in situ DNA polymerase I-mediated biotin-dATP nick-translation (PANT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), respectively. Levels of 8-OHdG and AP sites were markedly elevated 16-72 h following MCAO in the frontal cortex, representing the peri-infarct region, but levels did not significantly change within the ischemic core regions of the caudateputamen and parietal cortex. PANT- and TUNEL-positive cells began to be detectable 4-8 h following MCAO in the caudate-putamen and parietal cortex and reached maximal levels at 72 h. PANT- and TUNEL-positive cells were also detected 16-72 h after MCAO in the lateral frontal cortex within the infarct border, where many cells also showed colocalization of DNA single-strand breaks and DNA fragmentation. In contrast, levels of PANT-positive cells alone were transiently increased (16 h after MCAO) in the medial frontal cortex, an area distant from the infarct zone. These data suggest that within peri-infarct brain regions, oxidative injury to nuclear DNA in the form of base and strand damage may be a significant and contributory cause of secondary expansion of brain damage following permanent focal ischemia.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Glycine-extended gastrin synergizes with gastrin 17 to stimulate acid secretion in gastrin-deficient mice.

BACKGROUND & AIMS: Studies in gastrin-deficient mice have demonstrated critical roles for gastrin peptides in the regulation of gastric acid secretion, but the relative contributions of amidated (G-17) and glycine-extended (G17-Gly) gastrin remain unclear. We examined the effects of these 2 forms of gastrin on acid secretion in gastrin-deficient mice. METHODS: Sixty gastrin-deficient mice received infusions of saline, or 1, 6, or 14 days of amidated gastrin 17 (G-17), G17-Gly, or both G-17 and G17-Gly at 10 nmol. kg(-1). h(-1). Twenty-four gastrin-deficient mice were then infused for 14 days with 1, 2, or 5 nmol. kg(-1). h(-1) of G-17 or G-17 and G17-Gly. Acid secretion was determined 4 hours after pyloric ligation, and gastric tissue was processed for histology, immunohistochemistry, and electron microscopy. RESULTS: Infusion of G-17 increased acid secretion in a dose-dependent manner with a peak at 5 nmol. kg(-1). h(-1) and a subsequent decrease in acid secretion at higher doses. Infusion of G17-Gly alone had no effect on acid secretion, but coinfusion with G-17 resulted in significantly higher levels of acid secretion at all doses examined than infusion with G-17 alone. The potentiating effect of G17-Gly on G-17-induced acid secretion was associated with increased parietal cell activation but was independent of changes in parietal and enterochromaffin-like cell number, fundic proliferation rates, and H(+),K(+)-adenine triphosphatase expression. G17-Gly also prevented the formation of vacuolar canaliculi and lipofuscin bodies in the parietal cells induced by G-17. CONCLUSIONS: G17-Gly appears to synergize with G-17 to up-regulate acid secretion and prevent parietal cell degradation. These results suggest that G17-Gly plays an important role in parietal cell function.

Animals↗

PubMed2000

A preliminary study on intravenous infusion of sodium eicosapentaenoate.

Eicosapentaenoic acid (EPA) and arachidonic acid (AA), made into sodium salt solution (50 micrograms/ml), were used for intravenous infusion. In a preclinical study in dogs, Na-EPA lowered the activity of transminases (glutamic pyruvic transaminase [GPT], glytamic oxaloacetic transaminase [GOT]); however, Na-AA increased the activity of GPT and GOT. In the clinical study, the numbers of leukocytes and lymphocytes of volunteers increased and remained at that level for 3 to 5 days after intravenous infusion. The study indicated that an intravenous infusion of Na-EPA may have anti-inflammatory and immunomodulatory effects.

Animals↗

PubMed2000

Initiation of nucleolar assembly is independent of RNA polymerase I transcription.

This report examines the distribution of an RNA polymerase I transcription factor (upstream binding factor; UBF), pre-rRNA processing factors (nucleolin and fibrillarin), and pre-rRNAs throughout mitosis and postmitotic nucleologenesis in HeLa cells. The results demonstrate that nucleolin, fibrillarin, and pre-rRNAs synthesized at G2/M phase of the previous cell cycle are directly recruited to UBF-associated nucleolar organizer regions (NORs) early in telophase before chromosome decondensation. Unlike the fusion of prenucleolar bodies to the nucleoli, this early recruitment of processing factors and pre-rRNAs is independent of RNA polymerase I transcription. In the absence of polymerase I transcription, the initial localization of nucleolin, fibrillarin, and pre-rRNAs to UBF-associated NORs generates segregated mininucleoli that are similar to the larger ones observed in interphase cells grown under the same conditions. Pre-rRNAs are juxtaposed to UBF-nucleolin-fibrillarin caps that may represent the segregated nucleoli observed by electron microscopy. These findings lead to a revised model of nucleologenesis. We propose that nucleolar formation at the end of mitosis results from direct recruitment of processing factors and pre-rRNAs to UBF-associated NORs before or at the onset of rDNA transcription. This is followed by fusion of prepackaged prenucleolar bodies into the nucleolus. Pre-ribosomal ribonucleoproteins synthesized in the previous cell cycle may contribute to postmitotic nucleologenesis.

Cell Cycle↗

PubMed2000

Metabolic gene polymorphisms and risk of dysmenorrhea.

We conducted a molecular epidemiologic study in rural China to investigate the association of the cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase Mu (GSTM1) polymorphisms with dysmenorrhea. This report includes 435 subjects, 129 with and 306 without any history of dysmenorrhea, who did not smoke or drink alcohol. We obtained information on dysmenorrhea and major covariates by questionnaire interview. We used categorical methods and logistic regression models to evaluate the individual and combined associations of CYP2D6 and GSTM1 polymorphisms with dysmenorrhea and its subgroups, occasional (N = 70) and recurrent (N = 59), with adjustment for age, education, occupation, passive smoke exposure, age of menarche, parity, contraceptive method, height, and body mass index. Both variant CYP2D6 and GSTM1 genotypes were associated with increased risk of recurrent dysmenorrhea [for CYP2D6, odds ratio (OR) = 1.7 and 95% confidence interval (95% CI) = 0.9-3.1; for GSTM1, OR = 1.8 and 95% CI = 1.0-3.4). There was no appreciable association between these variant genotypes and occasional dysmenorrhea. When both the CYP2D6 and GSTM1 genotypes were considered together, the highest risk of recurrent dysmenorrhea was found among women with variant genotypes in both CYP2D6 and GSTM1 (OR = 3.1; 95% CI = 1.2-8.0). This study provides evidence of genetic susceptibility to recurrent dysmenorrhea.

Adult↗

PubMed2000

Overexpression of the cell death suppressor Bcl-w in ischemic brain: implications for a neuroprotective role via the mitochondrial pathway.

Bcl-w is a newly described cell death suppressor member of the Bcl-2 gene family. As these genes may have a role in the outcome of ischemic brain injury, the regional expression of Bcl-w protein in rat brain was examined at 6 to 72 hours after 90 minutes of transient middle cerebral artery occlusion. Bcl-w protein, although constitutively expressed at low levels in nonischemic brain, was found to be overexpressed in ischemic brain at all time points studied. Up-regulation of Bcl-w protein was particularly abundant in the penumbral region of the cortex and mainly in cells lacking DNA fragmentation. In the cortical penumbra, Bcl-w protein was detected predominantly in neurons and showed mitochondrial localization, as determined using double-label immunohistochemistry. Bcl-w expression was also detectable, to a lesser extent, in reactive astrocytes in the infarct border zone and in microvessel walls in the infarct regions. At the mechanistic level, incubation of isolated brain mitochondria with the addition of recombinant Bax or high concentration of calcium resulted in release of cytochrome c from the mitochondria. In the presence of recombinant Bcl-w protein, however, the release of cytochrome c induced by Bax or calcium was largely inhibited. Further, recombinant Bcl-w protein inhibited calcium-induced loss of mitochondrial transmembrane potential, indicative of permeability transition, in a dose-dependent manner. These results suggest that Bcl-w may be an endogenous neuroprotectant against ischemic neuronal death and that, like its analogues such as Bcl-2 and Bcl-x-long, Bcl-w may achieve this protection via the mitochondrial death-regulatory pathway.

Animals↗

PubMed2000

Delayed toe transplantation: experimental study and clinical application.

Delay of the operation in toe transplantation was performed with circulatory crisis, and 100 percent survival of the transplants was achieved. In 10 cases of toe transplantation in which circulatory crisis occurred, the operation was delayed. The vascular pedicle was divided, and the toe was transferred 17 to 21 hours after the donor toe was dissected. To investigate the mechanism of delayed toe transplantation, experiments in rabbits were carried out. In 36 rabbits, the hind limbs were severed except for the vascular pedicle. The endothelin content and nitric oxide content of the tissues in the hind limb and the arterial wall were tested in postoperative intervals of 4, 8, 16, 24, and 48 hours, respectively. The results showed that in 10 cases of delayed toe transplantation, all toes survived. As for the results of the experiment, there was significant increase of endothelin content and decrease of nitric oxide content in the local tissues and the arterial wall 4 to 8 hours after the operation. In postoperative 16 to 24 hours, endothelin content returned to normal level, and nitric oxide content increased remarkably. It is concluded that delayed pedicle division and toe transfer is an effective method in toe transplantation with vascular variations and circulatory crisis. The mechanism is related to the endothelin and nitric oxide content in the local tissue and the arterial wall. The indications for delayed toe transfer are also discussed.

Adolescent↗

PubMed2000

A novel approach to extract colon lumen from CT images for virtual colonoscopy.

An automatic method has been developed for segmentation of abdominal computed tomography (CT) images for virtual colonoscopy obtained after a bowel preparation of a low-residue diet with ingested contrast solutions to enhance the image intensities of residual colonic materials. Removal of the enhanced materials was performed electronically by a computer algorithm. The method is a multistage approach that employs a modified self-adaptive on-line vector quantization technique for a low-level image classification and utilizes a region-growing strategy for a high-level feature extraction. The low-level classification labels each voxel based on statistical analysis of its three-dimensional intensity vectors consisting of nearby voxels. The high-level processing extracts the labeled stool, fluid and air voxels within the colon, and eliminates bone and lung voxels which have similar image intensities as the enhanced materials and air, but are physically separated from the colon. This method was evaluated by volunteer studies based on both objective and subjective criteria. The validation demonstrated that the method has a high reproducibility and repeatability and a small error due to partial volume effect. As a result of this electronic colon cleansing, routine physical bowel cleansing prior to virtual colonoscopy may not be necessary.

Adult↗

PubMed2000

Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyltransferase gene.

Peptide deformylase, a bacterial enzyme, represents a novel target for antibiotic discovery. Two deformylase homologs, defA and defB, were identified in Staphylococcus aureus. The defA homolog, located upstream of the transformylase gene, was identified by genomic analysis and was cloned from chromosomal DNA by PCR. A distinct homolog, defB, was cloned from an S. aureus genomic library by complementation of the arabinose-dependent phenotype of a P(BAD)-def Escherichia coli strain grown under arabinose-limiting conditions. Overexpression in E. coli of defB, but not defA, correlated to increased deformylase activity and decreased susceptibility to actinonin, a deformylase-specific inhibitor. The defB gene could not be disrupted in wild-type S. aureus, suggesting that this gene, which encodes a functional deformylase, is essential. In contrast, the defA gene could be inactivated; the function of this gene is unknown. Actinonin-resistant mutants grew slowly in vitro and did not show cross-resistance to other classes of antibiotics. When compared to the parent, an actinonin-resistant strain produced an attenuated infection in a murine abscess model, indicating that this strain also has a growth disadvantage in vivo. Sequence analysis of the actinonin-resistant mutants revealed that each harbors a loss-of-function mutation in the fmt gene. Susceptibility to actinonin was restored when the wild-type fmt gene was introduced into these mutant strains. An S. aureus Deltafmt strain was also resistant to actinonin, suggesting that a functional deformylase activity is not required in a strain that lacks formyltransferase activity. Accordingly, the defB gene could be disrupted in an fmt mutant.

Amidohydrolases↗

PubMed2000

Genetic vaccination against malaria infection by intradermal and epidermal injections of a plasmid containing the gene encoding the Plasmodium berghei circumsporozoite protein.

The circumsporozoite protein (CSP) from the surface of sporozoite stage Plasmodium sp. malaria parasites is among the most important of the malaria vaccine candidates. Gene gun injection of genetic vaccines encoding Plasmodium berghei CSP induces a significant protective effect against sporozoite challenge; however, intramuscular injection does not. In the present study we compared the immune responses and protective effects induced by P. berghei CSP genetic vaccines delivered intradermally with a needle or epidermally with a gene gun. Mice were immunized three times at 4-week intervals and challenged by a single infectious mosquito bite. Although 50 times more DNA was administered by needle than by gene gun, the latter method induced significantly greater protection against infection. Intradermal injection of the CSP genetic vaccine induced a strong Th1-type immune response characterized by a dominant CSP-specific immunoglobulin G2a (IgG2a) humoral response and high levels of gamma interferon produced by splenic T cells. Gene gun injection induced a predominantly Th2-type immune response characterized by a high IgG1/IgG2a ratio and significant IgE production. Neither method generated measurable cytotoxic T lymphocyte activity. The results indicate that a gene gun-mediated CS-specific Th2-type response may be best for protecting against malarial sporozoite infection when the route of parasite entry is via mosquito bite.

Animals↗

PubMed2000

Identification of a sequence element from p53 that signals for Mdm2-targeted degradation.

The binding of Mdm2 to p53 is required for targeting p53 for degradation. p73, however, binds to Mdm2 but is refractory to Mdm2-mediated degradation, indicating that binding to Mdm2 is not sufficient for degradation. By utilizing the structural homology between p53 and p73, we generated p53-p73 chimeras to determine the sequence element unique to p53 essential for regulation of its stability. We found that replacing an element consisting of amino acids 92 to 112 of p53 with the corresponding region of p73 results in a protein that is not degradable by Mdm2. Removal of amino acids 92 to 112 of p53 by deletion also results in a non-Mdm2-degradable protein. Significantly, the finding that swapping this fragment converts p73 from refractory to sensitive to Mdm2-mediated degradation supports the conclusion that the amino acids 92 to 112 of p53 function as a degradation signal. We propose that the presence of an additional protein recognizes the degradation signal and coordinates with Mdm2 to target p53 for degradation. Our finding opens the possibility of searching for the additional protein, which most likely plays a critical role in the regulation of p53 stability and therefore function.

Binding Sites↗

PubMed2000

Exposure to benzene, occupational stress, and reduced birth weight.

OBJECTIVES: The association between birth weight and exposure to benzene, work stress, and other occupational and environmental hazards was investigated. METHODS: In a large petrochemical industry, 792 pregnant workers were enrolled and followed up through delivery between May 1996 and December 1998. Exposure to benzene and other solvents was assessed by an industrial hygienist based on each woman's job title and workplace information. Other occupational and environmental exposures and personal information, including perceived work stress, exposure to noise, physical exertion at work, and passive smoking, were obtained by an interview questionnaire. Univariate and multivariate regression models were used to examine the individual and combined associations of occupational and environmental exposures with birth weight, with adjustment for major confounders including gestational age. RESULTS: In the univariate model, birth weight was negatively associated with exposure to benzene (-58 g (95% confidence interval (95% CI), -115 to -2)) and with work stress (-84 g (95% CI, -158 to -10)). In the multivariate model, there was a significant interaction between exposure to benzene and work stress relative to reduced birth weight, after adjustment for other environmental and occupational exposures and personal variables. Adjusted mean birth weight was 3445 g (95% CI 3401 to 3489) among those with neither exposure, 3430 g for those with exposure to benzene only, 3426 g for those with work stress only, and 3262 g (95% CI 3156 to 3369) for those with both exposures. In other words, there was 183 g (95% CI 65 to 301) reduction in birth weight among those with both exposure to benzene and work stress compared with those with neither exposure. Other work or environmental factors could not explain these findings. CONCLUSIONS: Low level exposure to benzene and work stress interact to reduce birth weight in this population.

Adult↗

PubMed2000

Regulation of cdk2 activity in endothelial cells that are inhibited from growth by cell contact.

Endothelial cells (ECs) are quiescent in normal blood vessels but undergo rapid bursts of proliferation after vascular injury and during angiogenesis. Here we show that the activity of cyclin-dependent kinase-2 (cdk2), a key regulator of the G1 and S phases of the cell cycle, is expressed at high levels in proliferating ECs but at low levels in ECs that are contact-inhibited for growth. Despite these differences in kinase activity, the protein levels of cdk2 and 1 of its activating subunits, cyclin E, are not modulated by these different growth conditions. The cdk inhibitor p27 is highly expressed in contact-inhibited but not proliferating ECs, whereas the level of cyclin A protein is preferentially expressed in proliferating ECs. p27 protein was detected in immunoprecipitable complexes with cdk2 or cyclin E in cultures that were contact-inhibited for growth. The functional significance of the p27 induction was indicated by the detection of a heat-stable cdk2 inhibitory activity that was induced by endothelial cell-cell contact and could be immunodepleted with anti-p27 antibodies. In a confluent EC monolayer, cdk2 kinase activity was activated by a scraping injury that led to cell migration and proliferation. The injury-induced activation of cdk2 coincided with the downregulation of p27 and the induction of cyclin A. These data demonstrate that p27 is induced in confluent cultures of ECs. They also indicate that both p27 induction and cyclin A downregulation contribute to the inhibition of cdk2 and cell proliferation by cell-cell contact in ECs.

Animals↗

PubMed2000

Cloning and characterization of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) from crayfish axial muscle. Sarco/Endoplasmic Reticulum Ca(2+)-ATPase.

The discontinuous pattern of muscle growth during the moulting cycle of a freshwater crustacean (the crayfish Procambarus clarkii) was used as a model system to examine the regulation of the expression of Sarco/Endoplasmic Reticulum Ca(2+)-ATPase (SERCA). We describe the cloning, sequencing and characterization of a novel SERCA cDNA (3856 bp) obtained from crayfish axial abdominal muscle by reverse transcription/polymerase chain reaction (RT-PCR) followed by rapid amplification of cDNA ends (RACE). This complete sequence contains a 145 base pair (bp) noncoding region at the 5' end, a 3006 bp open reading frame coding for 1002 amino acid residues with a molecular mass of 110 kDa and 705 bp of untranslated region at the 3' end. This enzyme contains all the conserved domains found in 'P'-type ATPases, and the hydropathy profile suggests a transmembrane organization typical of other SERCAs. It exhibits 80% amino acid identity with Drosophila melanogaster SERCA, 79% identity with Artemia franciscana SERCA, 72% identity with rabbit fast-twitch muscle neonatal isoform SERCA1b, 71% identity with slow-twitch muscle isoform SERCA2 and 67% identity with SERCA3. Sequence alignment revealed that regions anchoring the cytoplasmic domain in the membrane were highly conserved and that most differences were in the NH(2) terminus, the central loop region and the COOH terminus. Northern analysis of total RNA from crayfish tissues probed with the 460 bp fragment initially isolated showed four bands (7.6, 7.0, 5.8 and 4.5 kilobases) displaying tissue-specific expression. SERCA was most abundant in muscle (axial abdominal, cardiac and stomach), where it is involved in Ca(2+) resequestration during relaxation, and in eggs, where it may be implicated in early embryogenesis. The level of SERCA mRNA expression in axial abdominal muscle varied during the moulting cycle as determined by slot-blot analysis. SERCA expression was greatest during intermoult and decreased to approximately 50% of this level during pre- and postmoult. Patterns of gene expression for SERCA and other sarcomeric proteins during the crustacean moulting cycle may be regulated by ecdysteroids and/or mechanical stimulation.

Amino Acid Sequence↗

PubMed2000

Dose-effect relationship of dicentric and ring chromosomes in lymphocytes of individuals living in the high background radiation areas in China.

Chromosomes of 39 healthy family members (3 generations from 13 families) living both in the high-level background radiation areas (HBRA) and the control areas (CA) were studied. Cumulative dose from birth to the time of blood sampling was estimated by calculating measured exposure rate in each individual. The cumulative doses ranged 30.9-358.9 and 6.0-59.2 mGy for HBRA and CA, respectively. Peripheral lymphocyte chromosome preparations were made according to our improved method. Dicentric and ring chromosomes (Dic + Rc) were scored in average 2,527 cells per individual in HBRA and 2,694 cells in CA under a microscope equipped with an automated stage. A positive correlation between Dic + Rc and age was found in HBRA, while no such dose relationship was clear in CA. The frequency of Dic + Rc linearly increases over lifetime due to chronic low dose exposure and it is likely that the activation of repair enzymes is not triggered in the present HBRA. Threshold dose (rate) of the induction of chromosome aberrations, if any, is below the present dose (rate) level.

Adult↗

PubMed2000

Chromosome translocation in residents of the high background radiation areas in southern China.

We performed a cytogenetical study using chromosome painting analysis on 9 residents of the naturally high background radiation areas (HBRA) and 8 residents of the control areas in southern China. The estimated dose (air kerma) of each resident measured by an electric pocket dosimeter showed 2.20-4.23 mGy/year in HBRA and 0.56-0.70 mGy/year in the control areas. A total of 14,096 cells (1,566 cells/case) in the former and 17,522 cells (2,190 cells/case) in the latter were analyzed. Children, both in HBRA and in the control areas, had translocations at low frequencies. The frequency of translocations among elder individuals varied widely and it was not possible to detect dose effect although it was detected in dicentrics. The effect of radiation on the induction of chromosome aberrations, which have a statistically potential risk of causing malignant or congenital diseases, seems to be less significant than those of metabolic factors and/or mutagenic agents (excluding radiation) even in HBRA in China.

Aged↗

PubMed2000

Prospective study of exposure to environmental tobacco smoke and dysmenorrhea.

Dysmenorrhea is a common gynecologic disorder in women of reproductive age. Previous studies have found an association between current cigarette smoking and prevalence of dysmenorrhea. This study investigated the association between exposure to environmental tobacco smoke (ETS) and the occurrence of dysmenorrhea among women without a history of this disorder. The study population consisted of 165 newly wed, nonsmoking Chinese women (in Shenyang, China), who intended to get pregnant and who had no past history of dysmenorrhea at the time of enrollment. These women completed a baseline questionnaire interview upon enrollment and were prospectively followed by daily diary. Dysmenorrhea was defined as a diary recording of abdominal pain or low back pain for at least 2 days during a menstrual period. A subject's ETS exposure was defined as the mean number of cigarettes smoked per day at home by household members over an entire menstrual cycle before the menstrual period. A logistic regression model was used to assess the effect of ETS on the risk of dysmenorrhea, with adjustment for age, body mass index, education, season, area of residence, occupation, shift work, perceived stress, passive smoking at work, and occupational exposure to chemical hazards, dust, and noise. Generalized estimating equations were used to account for autocorrelations as a result of multiple cycles per subject. This report is based on 625 prospectively followed menstrual cycles with complete baseline and diary data. ETS exposure was reported in 77% of cycles, within which average daily exposures throughout the cycle ranged from 0.02 to 10. 3 cigarettes. The incidence of dysmenorrhea was 9.7% and 13.3% among nonexposed and exposed cycles, respectively. Among ETS-exposed cycles, there was a positive dose-response relationship between the numbers of cigarettes smoked and the relative risk of dysmenorrhea. The adjusted odds ratios of dysmenorrhea associated with "low," "middle," and "high" tertiles of ETS exposure versus no exposure were 1.1 [95% confidence interval (CI), 0.5-2.6], 2.5 (CI, 0.9-6.7), and 3.1 (CI, 1.2-8.3), respectively. The findings were consistent with those of analyses limited to the first follow-up menstrual cycle from each woman. These data suggest a significant dose-response relationship between exposure to ETS and an increased incidence of dysmenorrhea in this cohort of young women.

Adult↗

PubMed2000

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

Child↗