Lungs Of Offspring Research Articles

Guest Editorial: Biomarkers of Perfluorinated Chemicals and Birth Weight

Guest Editorial: Biomarkers of Perfluorinated Chemicals and Birth Weight

A new assay system for evaluation of developmental immunotoxicity of chemical compounds using respiratory syncytial virus infection to offspring mice

We evaluated the effect of 6-propyl-2-thiouracil (PTU), an anti-thyroid agent, on developmental immunity using respiratory syncytial virus (RSV) infection to offspring mice as a new risk assessment for brominated flame retardants (BFRs), because some BFRs are suspected of affecting the thyroid system. Pregnant mice were exposed to PTU in drinking water from gestation day 10 to weaning on postnatal day 21. Their offspring mice were infected intranasally with RSV. Exposure of 100 ppm PTU significantly increased virus titers in the lungs of RSV-infected offspring compared with the control, and the 10 ppm also elevated levels of interferon-γ, a marker of pneumonia, in the bronchoalveolar lavage fluids of offspring. Histopathological analysis revealed that PTU-exposure exacerbated pneumonia in RSV-infected offspring. Thus, exacerbation of RSV infection suggested PTU-exposure of dams elicited developmental immune disorder in the offspring. The murine RSV infection model may be useful to evaluate the developmental immunotoxicity of BFRs.

The Role of Carnosine in Protection Against the Damaging Effect of Maternal Nicotine Exposure During Gestation and Lactation on the Lung of Albino Rat Offspring

The Role of Carnosine in Protection Against the Damaging Effect of Maternal Nicotine Exposure During Gestation and Lactation on the Lung of Albino Rat Offspring

Vitamin C Prevents the Effects of Prenatal Nicotine on Pulmonary Function in Newborn Monkeys

Smoking during pregnancy leads to decreased pulmonary function and increased respiratory illness in offspring. Our laboratory has previously demonstrated that many effects of smoking during pregnancy are mediated by nicotine. We now report that vitamin C supplementation can prevent some of the effects of maternal nicotine exposure on pulmonary function of offspring. Timed-pregnant rhesus monkeys were treated with 2 mg/kg/day nicotine bitartrate from Gestation Days 26 to 160. On Gestation Day 160 (term, 165 days) fetuses were delivered by C-section and subjected to pulmonary function testing the following day. Nicotine exposure significantly reduced forced expiratory flows, but supplementation of mothers with 250 mg vitamin C per day prevented the effects of nicotine on expiratory flows. Vitamin C supplementation also prevented the nicotine-induced increases in surfactant apoprotein-B protein. Neither nicotine nor nicotine plus vitamin C significantly affected levels of cortisol or cytokines, which have been shown to affect lung development and surfactant expression. Prenatal nicotine exposure significantly decreased levels of elastin content in the lungs of offspring, and these effects were slightly attenuated by vitamin C. These findings suggest that vitamin C supplementation may potentially be clinically useful to limit the deleterious effects of maternal smoking during pregnancy on offspring's lung function.

Maternal glutathione S‐transferase GSTP1 genotype is a specific predictor of phenotype in children with asthma

Maternal factors are known to influence the heritability and expression of asthma and atopy. We report the association of maternal, paternal and proband GSTP1 genotype with lung function in 145 Caucasian children with asthma. GSTP1 Val105/Val105 and Ala114/Val114 genotypes in the child were associated with non-significant increases in lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the FEV1/FVC ratio). Paternal genotype had no influence on lung function in the child. In contrast, maternal GSTP1 Val105/Val105 genotype was significantly associated with offspring lung function and was strongly predictive of FEV1/FVC (Val105/Val105 105.2%, Ile105/Val105 and Ile105/Ile105 97.9% p=0.006) and maternal GSTP1 Ala114/Val114 genotype was associated with significantly higher FEV1 (Ala114/Val114 109.0%, Ala114/Ala114 99.0% p=0.008), and FEV1/FVC ratios (Ala114/Val114 104.1%, Ala114/Ala114 98.2% p=0.04). The associations between maternal GSTP1 Val105/Val105 genotype and FEV1/FVC and maternal GSTP1 Ala114/Val114 genotype and FEV1 remained significant (p=0.003 and p=0.007) after correction for child and maternal atopic status, passive smoke exposure, smoking during pregnancy, individual and paternal GSTP1 genotype and was independent of transmission to the child. These data support the hypothesis that maternal GSTP1 genotype can act as a specific risk factor which has ex utero consequences for children with asthma. As a child's genotype is not independent of maternal genotype, effects seen in candidate gene studies may be due at least in part to this phenomenon.

Parental allergic status influences the risk of developing allergic sensitization and an asthmatic-like phenotype in canine offspring.

Increasing evidence suggests that parental allergic status, especially that of the mother, may play a unique and important role in influencing the development of fetal infant immune responses to inhaled allergens, independently of genetic predisposition. We have developed an experimental model in dogs where the offspring from allergic parents, when exposed to inhaled allergen, develop allergic sensitization and an asthmatic phenotype, whereas the offspring from non-allergic parents do not. Offspring from ragweed-sensitized (two litters, n = 10) or non-sensitized (two litters, n = 11) Beagle dogs were exposed repeatedly, by inhalation, to ragweed or filtered air (negative control) beginning within 1 week after birth. Serum levels of total immunoglobulin (Ig)E, and ragweed-specific IgE and IgG, were measured at specific time-points up to 40 weeks after birth. Cell differentials in the bronchoalveolar lavage were determined on days 1 and 4 following ragweed instillation into the offspring's lungs at 26 weeks of age. Changes in pulmonary resistance following challenge with histamine and ragweed (five breaths) were measured at 40 weeks after birth. Offspring from sensitized parents exposed to ragweed developed elevated serum total IgE and ragweed-specific IgE and IgG, and showed an increased pulmonary resistance to histamine and ragweed, and increased numbers of eosinophils in bronchoalveolar lavage. In contrast, offspring from non-sensitized parents did not exhibit this immune response. These results suggest that parental allergic sensitivity is important in the development of allergic sensitization and an asthmatic phenotype in the offspring.

Ontogeny and nutritional manipulation of mitochondrial protein abundance in adipose tissue and the lungs of postnatal sheep.

The present study examined the ontogeny of mitochondrial protein abundance in adipose tissue and lungs over the first month of life in the sheep and the extent to which this may be altered by maternal undernutrition during the final month of gestation. The ontogeny of uncoupling protein (UCP), voltage-dependent anion channel (VDAC) and cytochrome c abundance were determined in adipose tissue and lungs sampled from near-term fetuses and young sheep aged 4 h, 1, 7 and 30 d. In adipose tissue, the abundance of UCP1, VDAC and cytochrome c all peaked at 1 d of age and then decreased by 30 d of age, at which stage the brown adipose tissue-specific UCP1 was no longer detectable but UCP2 was clearly abundant. For the lungs, however, UCP2 and VDAC abundance both peaked 7 d after birth and then decreased by 30 d of age. During postnatal development, therefore, a marked change in mitochondrial protein abundance occurs within both adipose tissue and lungs. Maternal nutrient restriction had no effect on lamb growth or tissue weights at 30 d of age but was associated with increased abundance of UCP2 and VDAC but not cytochrome c in both adipose tissue and lungs. These mitochondrial adaptations within both adipose tissue and the lungs of offspring born to previously nutrient-restricted mothers may compromise adipose tissue and lung function during periods of environmental stress.

Pulmonary CYP1A1 and CYP1A2 levels and activities in adult male and female offspring of rats exposed during gestation and lactation to 2,3,7,8-tetrachlorodibenzo- p-dioxin

The levels and activities of pulmonary microsomal CYP1A1 and CYP1A2 in 40-day-old male and female, and 120-day-old male offspring of pregnant rats treated with five weekly 0.1 μg/kg doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) during gestation and lactation were compared with those in age-matched offspring of untreated dams. The CYP1A1-preferential activity, ethoxyresorufin O-deethylase (EROD), was comparably induced 5.3- and 6.4-fold in 40-day-old male and female offspring, respectively, but was not induced in 120-day-old male offspring, of TCDD-treated dams. Similarly, CYP1A1 protein was induced in 40-day-old female or male offspring of untreated dams but was undetectable in 120-day-old offspring of untreated or treated dams. CYP1A2 activity, as measured by the bioactivation of 2-amino-3,4-dimethylimidazo[4,5- f]quinoline (MeIQ) to mutagens in the Ames assay, was elevated 11.1- and 5.5-fold in 40-day-old female and male offspring, respectively, of TCDD-treated dams, but was unaffected by TCDD exposure in 120-day-old offspring. CYP1A2 protein was undetectable in 40-day-old male or female offspring of untreated dams or in 120-day-old male offspring of treated or untreated dams; it was detected in 40-day-old offspring of treated dams, at a level that was higher in females than in males. The results show that gestational and lactational exposure to TCDD causes long-lasting and gender-preferential induction of CYP1A1 as well as CYP1A2 in the lungs of rat offspring.

Sex- and organ-specific toxicity in normal and malnourished rats fed thermoxidized palm oil

The effects of free radical toxicity as induced by chronic consumption of thermoxidized palm oil (TPO) diet on organ size of normal animals, their first filial offspring and malnourished rats, were studied. Tissue- and sex-specific toxicity was revealed. The TPO diet significantly ( P<0.01) reduced lung and kidney mass in normal male rats but female rats remained unaffected. Hearts of first filial offspring of both male and female rats were, however, enlarged while lung, liver and kidneys of first filial female offspring were additionally reduced in size ( P<0.01). This information suggests that the observed toxicities could be cumulative for female offspring. Malnutrition protected against toxic injury because none of the kwashiorkoric animals rehabilitated on the toxic diet showed any overt symptoms of toxicity.

Developmental control of collagen gene expression in the rat lung: confirmation of early observations of lung growth.

The short gestation period of the rat allows one to see rapid morphologic and biochemical changes in the lung. It has been shown that the rat lung undergoes a period of distension over the first several days of life followed by a rapid alveolar growth. Total lung collagen also increases during this time period. We have examined the changes in types I and III procollagen transcripts during the perinatal period and have compared them to the above observations. Total RNA was extracted from the lungs of offspring of time-pregnant Sprague-Dawley rats after large airways were removed. Northern hybridization was performed to determine the quality of steady-state RNA and rule out cross-hybridization while densitometric tracings of slot-blot hybridizations allowed comparative estimates of the target sequence of RNA. Immediately following birth, the steady-state mRNA procollagen levels increased and a shift to a predominant type I production occurred. These changes preceded the rapid increase of collagen content and alveolarization known to occur at three days of age. These data provide further evidence that collagen production is controlled at the level of transcription and in temporal and tissue-specific manners.

The role of the nonciliated bronchiolar epithelial (Clara) cell as the progenitor cell during bronchiolar epithelial differentiation in the perinatal rabbit lung.

Although it is well established that the nonciliated bronchiolar epithelial (Clara) cell serves as the progenitor for itself and ciliated cells in the adult lung following bronchiolar epithelial injury, the nature of this relationship during development has not been well characterized. To define the pattern of proliferation and differentiation of bronchiolar ciliated and nonciliated cells, lungs of fetuses and offspring from time-mated New Zealand White rabbits, ranging in age from 24 days of gestation to 25 wk postnatal (PN), were fixed by airway infusion and embedded for simultaneous light and transmission electron microscopy. Three categories of cells could be distinguished in terminal bronchioles: nonciliated cells with abundant glycogen and variable numbers of organelles; nonciliated cells with little glycogen, large numbers of polyribosomes, and variable numbers of basal bodies; and ciliated cells with cilia of varying height. Together, both types of nonciliated cells were 100% of the epithelium at 24 and 27 days gestation age (DGA). At 30 days DGA, they were 85% of the population; at all postnatal ages, they ranged from 75 to 81% of the total population. Nonciliated cells with polyribosomes and basal bodies were 10 to 20% of the total nonciliated cell population between 24 DGA and 1 wk PN and not found thereafter. Ciliated cells were not observed in animals younger than 30 DGA. Labeling indices of bronchiolar epithelium in fetuses of pregnant rabbits injected with tritiated thymidine, as determined by autoradiography, were 57 cells per thousand at 28 DGA (1 h postinjection [PI]), 76 at 29 DGA (24 h PI), and 114 at 30 DGA (48 h PI).(ABSTRACT TRUNCATED AT 250 WORDS)

High-performance liquid chromatographic analysis of lung phospholipids and their precursors in the offspring of diabetic rats

Pulmonary phospholipids and their precursors and metabolites were assayed in the offspring of streptozotocin-induced diabetic rats at 19 and 21 days gestation and at 2 days after birth by two unique methods that employ high performance liquid chromatography combined with automated phosphorus analysis. In general, lung phospholipids were not different between offspring of control versus diabetic mothers. Levels of phosphatidylglycerol, however, were decreased in the offspring of diabetics. Lysophosphatidylcholine appears to be increased in the lungs of offspring of diabetic mothers, suggesting that maternal diabetes is associated with alterations in the remodeling of phosphatidylcholine.

Effects of paraquat on reproduction and mortality in two generations of mice.

Studies were made on the effects of paraquat on reproduction and mortality in two generations of mice (Mus musculus). Paraquat was administered in food at 0, 45, 90, and 125 mg/kg for both generations. In the first generation phase, paraquat was administered continually to mature mice beginning before pregnancy, with exposure to the F1 to 49 days after birth. Parent (P) mice in the second generation were F1 individuals and were continually exposed prenatal and postnatal to paraquat. Second generation control and 125 mg/kg F2 were continued on their respective diets to 49 days after birth. Variables examined included females' age to first and second parturitions, number born per litter, offspring abnormalities, and P and offspring mortality. Lung tissue was also examined for abnormalities. No differences were observed in the females' age at the first parturition, number born per litter, or offspring abnormalities. However, paraquat treatment at 125 mg/kg produced significant (P<0.05) effects on the females' age at the second parturition, first generation P female and F1 mortality, and P female and offspring lung tissue. Second generation mice were more resistant to paraquat poisoning than those in the first generation. The results suggest possible toxic effects that might occur with the commercial use of paraquat.

Serum acute phase reactants in necrotising enterocolitis : David Isaacs, Jonathan North, David Lindsell and Andrew Wilkinson. Departments of Paediatrics, Immunology and Radiology. John Radcliffe Hospital, Oxford

Studies have demonstrated that maternal consumption of a high fat diet (HFD) increases offspring susceptibility to metabolic disease. This study was initiated to identify the mechanistic contribution of oxidative stress on this phenomenon. Two weeks prior to mating, dams were fed either HFD or Control diet with or without supplementation with the anti-oxidant N-acetylcysteine (NAC). Pups born to HFD dams had reduced crown rump length (CRL) at birth and higher neonatal mortality compared to pups from Control dams. Supplementation with NAC normalized CRL in pups from HFD dams, but notably increased mortality. Histological examination of the lungs postnatally and prenatally, revealed normal branching morphogenesis but delayed alveolarization in pups from dams fed HFD + NAC. Discontinuation of NAC at ED17.5 with re-introduction at PD3 improved offspring survival and lung maturation. Additionally, interscapular brown adipose tissue (BAT) was reduced in ED18.5 embryos from HFD dams. These findings suggest that increased mortality in offspring from dams fed HFD + NAC during pregnancy may in part be the result of delayed pulmonary alveolarization and decreased BAT.

Metyrapone delays surfactant and antioxidant enzyme maturation in developing rat lung.

The surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and both can be accelerated by the administration of exogenous glucocorticoids. To test whether the antioxidant enzyme system, like the surfactant system, is regulated, at least in part, by endogenous glucocorticoids, we injected pregnant rats for 3 days prior to delivery with metyrapone, an adrenal 11-beta hydroxylase inhibitor which crosses the placenta and blocks endogenous glucocorticoid synthesis, or saline. Metyrapone offspring had significantly decreased lung tissue disaturated phosphatidylcholine/total phospholipids (p less than 0.05) compared to controls at days 21 and 22 of gestation. Activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were similarly significantly reduced (p less than 0.01) in the lungs of metyrapone offspring at both gestational days studied. One day premature metyrapone pups demonstrated poorer survival than control pups from 25 min after delivery (44% survival versus 83%, p less than 0.05) to 90 min (6% survival versus 78%, p less than 0.01). These findings of delayed maturation of the surfactant and antioxidant enzyme systems following adrenal glucocorticoid blockade suggest that both systems are regulated, at least in part, by an endogenous glucocorticoid mechanism.

Effects of maternal diabetes on the levels, synthetic rates and activities of synthetic enzymes of surface-active phospholipids in perinatal rat lung

Streptozotocin-induced maternal diabetes in the rat has been found to reduce selectively the content and synthetic rates of disaturated phosphatidylcholine and lysophosphatidylcholine in the lungs of term fetuses. Furthermore, the elevations in these parameters which occur during normal pulmonary maturation between the final gestational day and the first neonatal day are abolished or markedly curtailed, resulting in significantly reduced levels and synthetic rates of surfactant and its immediate precursor in the neonatal lung. In addition, complete or partial inhibition of the perinatal developmental rise in the activities of key enzymes catalyzing de novo phosphatidylcholine synthesis in the lung, viz., cholinephosphate cytidylyltransferase and cholinephosphotransferase and of enzymes catalyzing reacylation of unsaturated to disaturated phospholipid, viz., lysophosphatidic acid and lysophosphatidylcholine acyltransferases, has been observed, resulting in reduced activities of these enzymes in the neonate. The observed reductions in surface-active phospholipid synthesis in the lungs of offspring of diabetic mothers may be related to these lowered enzyme activities, as well as to deficiencies in carbohydrate precursors available for phospholipid synthesis, as reported in previous studies. It is suggested that the hyperinsulinemia manifested in fetuses of diabetic mothers opposes the tendency of corticosteroids to enhance surface-active phospholipid synthesis, resulting in pulmonary surfactant deficiency and thus the propensity for neonatal respiratory distress.

Transplacental effects of carcinogens and non-carcinogens on activities of pyruvate kinase and lactate dehydrogenase as well as isozymic pattern of LDH in mouse lung

The carcinogens, urethane (URTH), 3-methylcholanthrene (MCA) and dimethylnitrosamine (DMN) given to pregnant mice enhanced permanently the activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH) in the lungs of offspring even well before the appearance of lung tumours. The noncarcinogenic analogues phenylurethane (PHUR) and pyrene (PYR), had no effect on PK or LDH activity. The non-carcinogenic pulmonary toxicant Paraquat (PAR) elicited only a temporary elevation in the activities of the enzymes tested. The H : M ratio of LDH sub-units in the lungl tissue was permanently decreased by URTH administered transplacentally. PAR caused only a temporary decrease in the H : M ratio, while PHUR had no effect on the isozymic pattern of LDH.