Severe bronchopulmonary dysplasia increases risk for later neurological and motor sequelae in preterm survivors

Preterm children who develop severe chronic lung disease may be developmentally compromised by exposure to hypoxic episodes. This study aims to determine if children with severe bronchopulmonary dysplasia (BPD) who required home oxygen therapy were at greater risk for neurological and motor deficits at school age than preterm peers without BPD. This study evaluated 27 subjects with BPD and 27 preterm control infants matched for gestational age, birthweight, sex, and year of birth at a mean age of 9.9 years (2.0 SD) using standardized neuromotor outcome measures. Pair-matched comparisons and regression analyses were used to determine if subjects with BPD were at increased risk for neuromotor sequelae. Neurological abnormalities, including subtle neurological signs, cerebral palsy, microcephaly, and behavioral difficulties were highly prevalent in the BPD group (71% compared with 19% in control group, P<0.005). Over half the BPD cohort had difficulties in gross and/or fine motor skills. There were significant differences in postural stability between groups. Duration of hospitalization and home oxygen treatment, and decreased lung function at school age, markers of severity of illness, correlated with motor outcomes. The findings underline the importance of preventing the cardiorespiratory complications associated with chronic lung disease to minimize disability in preterm children. For children with severe BPD, better recognition and subsequent remediation of neuromotor impairments that manifest at school age may help maximize their functional potential.     

The fate of isoprene inhaled by rats: comparison to butadiene

Isoprene (2-methyl-1,3-butadiene), a volatile monomer occurring in the natural environment and used in the manufacture of elastomers, is a close chemical relative of the animal carcinogen 1,3-butadiene. To obtain toxicokinetic data for inhaled isoprene, male F344 rats were exposed in groups of 30 to 14C-labeled isoprene vapor at four concentrations from 8 to 8200 ppm. The percentage of the inhaled isoprene that was metabolized decreased with increasing exposure concentration. The percentage of the total metabolites (that is, non-isoprene-retained 14C) excreted in urine and feces or expired was determined as a function of vapor concentration. About 75% of the total metabolites was excreted in urine. This was independent of inhaled isoprene concentration. After exposure to 8200 ppm, a larger percentage of the metabolites was excreted in feces than after exposure to lower concentrations. Using vacuum line techniques, blood metabolite concentrations were determined as functions of both vapor concentration and exposure duration. At one exposure concentration (1480 ppm) metabolites were measured in the nose, lungs, liver, kidney, and fat, as well as in blood. A mutagenic metabolite, isoprene diepoxide, was tentatively identified in all tissues examined. Between 0.0018 and 0.031% of the inhaled 14C label was tentatively identified as this metabolite in blood. The relative amount of the metabolites present in blood was highest for low concentrations of inhaled isoprene and for shorter exposure durations. Body fat appeared to be a reservoir for both isoprene metabolites and isoprene itself. The appearance of metabolites in the respiratory tract after short exposure durations together with low blood concentrations of isoprene indicated that substantial metabolism of inhaled isoprene in the respiratory tract may occur.     

The influence of aging on intestinal absorption of TCDD in rats

The effects of age on intestinal absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied using adult male Fischer-344 rats of 3 different age groups: 13 weeks old (young), 13 months old (mature), and 26 months old (senescent). Absorption was measured with an in situ intestinal recirculation perfusion procedure. Absorption expressed in terms of ng TCDD absorbed/g intestinal dry weight/h was 166, 149 and 143 ng/g/h in the young, mature and senescent groups, respectively. When absorption was calculated in terms of ng TCDD absorbed/g mucosal dry weight/h, the decrease between the senescent rats and the 2 younger age groups, from 544 ng/g/h (young) to 351 ng/g/h (senescent), was not statistically significant (P less than 0.05). It was demonstrated that absorption of TCDD was unaffected by the presence of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) in the perfusate, but that HCB absorption was (P less than 0.01) enhanced by the presence of TCDD.     

Teratogenic effects of polychlorinated dibenzofurans in combination in C57BL/6N mice

Polychlorinated dibenzofurans (PCDFs) are highly toxic environmental contaminants which have been involved in several incidents of human poisoning. Two congeners, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), have been shown to persist in the tissues of victims of accidental ingestion from Japan and Taiwan. The teratogenicity of these compounds, both alone and in combination, was assessed in C57BL/6N mice. Pregnant mice were treated with 10 ml/kg corn oil containing no PCDFs, 4-PeCDF (0-30 micrograms/kg), HCDF (0-300 micrograms/kg), or a combination of the two on gestation Days 10-13, followed by necropsy on gestation Day 18. Maternal and fetal toxicity were assessed and selected soft tissues were examined for abnormalities. Both chemicals caused hydronephrosis and cleft palate in the absence of any overt toxicity. Hydronephrosis occurred at doses approximately fivefold lower than those causing cleft palate. The combination of 4-PeCDF and HCDF was additive for terata based on responses predicted by probit analysis. In addition, the combination of 2,3,4,5,3',4'-hexachlorobiphenyl (0-60 mg/kg), a structurally related compound also present in PCDF poisoning victims, and 4-PeCDF appears additive. Thus, these chemicals, which cause toxic effects similar to those of 2,3,7,8-tetrachlorodibenzo-p-dioxin, are additive in the induction of fetal anomalies in the mouse.     

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Effect of o-benzyl-p-chlorophenol on drug-metabolizing enzymes in rats

o-Benzyl-p-chlorophenol (BCP) is widely used as a broad spectrum disinfectant. Treatment of male Fischer 344 rats with BCP resulted in an increase in cytochrome P-450 content and an accompanying decrease in aryl hydrocarbon hydroxylase (AHH) activity in both liver and kidney microsomes. Several other drug-metabolizing enzymes were not affected by BCP treatment. However, in kidney, BCP induced NADPH-cytochrome c reductase and uridine diphosphate glucuronyl transferase activities and caused a small increase in total cytochrome P-450 content and glutathione concentration. The cytochrome P-450 isozymes induced by BCP were fractionated by high pressure liquid chromatography (HPLC). The HPLC profile following BCP treatment most closely resembled that seen after phenobarbital. Using an immunoblotting procedure and a radioimmunoassay, it was shown that the increase in cytochrome P-450 content in the liver after BCP treatment was, in part, due to an increase in the phenobarbital-inducible isozymes, P-450b + e. In the kidney, the increase in total cytochrome P-450 content after BCP exposure was not due to an increase in P-450b + e. The decrease in AHH activity appeared to be caused by noncompetitive inhibition of constitutive AHH activity by BCP. BCP also inhibited benzphetamine demethylation, although to a lesser extent. The failure to observe an increase in benzphetamine demethylase activity in vivo, despite the induction of P-450b, was probably due to the concomitant induction and inhibition of drug-metabolizing enzymes by BCP.