Spatial and Temporal Expression of Glucocorticoid, Retinoid, and Thyroid Hormone Receptors Is Not Altered in Lungs of Congenital Diaphragmatic Hernia

Rajatapiti, Prapapan; Keijzer, Richard; Blommaart, Pietjan E; Lamers, Wouter H.; Krijger, Ronald R. de; Visser, Theo J.; Tibboel, Dick; Rottier, Robbert J.

doi:10.1203/01.pdr.0000246245.05530.02

Cited by 21 publications

(21 citation statements)

References 43 publications

(52 reference statements)

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“…Quantitative PCR data showed that the expression of cellular binding protein mRNA was unaffected by nitrofen. Furthermore, the expression of RA receptor mRNA was not decreased, which is consistent with the report of Rajatapiti et al (55) from analyses of lung tissue in both the nitrofen model and human CDH. This, however, differs from a previous report of an almost complete abolition of Rar␣ and Rar␤ mRNA expression in nitrofen-exposed fetal mice (15).…”

Section: Discussionsupporting

confidence: 91%

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Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

Noble

Babiuk²,

Clugston³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported. retinoid signaling CONGENITAL DIAPHRAGMATIC HERNIA (CDH) is a serious developmental abnormality that occurs in ϳ1 in 2,500 live births (41). The most commonly observed type of this anomaly is the Bochdalek hernia, characterized by incomplete formation of the posterolateral diaphragm and the invasion of the thoracic cavity by abdominal viscera. The ensuing abnormal fetal breathing movements and physical constraints on the developing lungs and heart contribute to pulmonary and left ventricular hypoplasia and pulmonary hypertension (20,35,37). Despite improved treatment strategies, CDH continues to have significant morbidity and mortality (50,69). Insights into the pathogenesis of the diaphragm defect have arisen from teratogenic, dietary, and genetic rodent models of Bochdalek CDH in conjunction with examination of human postmortem tissue (17). Specifically, the initial diaphragmatic defect appears to occur early (before week 5) during the embryogenesis of the amuscular component of the primordial diaphragm, the pleuroperitoneal fold. Much less is known about the etiology of CDH. However, considering the partial similarities between the pathologies observed in the teratogenic nitrofen-induced rat model and infants with CDH (1, 19, 40), the possibility that a common underlying etiology exists has received consideration. There have been a number of hypotheses put forth to explain the teratogenic effects of nitrofen. The retinoid hypothesis suggests that abnormalities in retinoid signaling, or regulation of the retinoid pathway, lead to the development of the primary diaphragm defect and potentially to direct effects on lung development (reviewed in Ref. 33). Other studies have suggested that nitrofen alte...

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Section: Discussionsupporting

confidence: 91%

“…Teramoto et al (61) reported a nitrofen-induced decrease expression of Tr␣1 and Tr␤1 in rat lungs compared with controls. However, a more recent study examining both nitrofen-exposed embryonic rat lung and human lungs from CDH cases reported no change in TR␣ and TR␤ protein or mRNA expression (55).…”

Section: Discussionmentioning

confidence: 94%

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

Noble

Babiuk²,

Clugston³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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“…Nowadays, cells can be stored for a prolonged time, so cells derived from biopsies as well as the tissues itself could be stored to create a biobank for future research when new investigative techniques such as whole genome sequencing become available, or new results from animal studies warrant translation to the human situation. Our biobank of lung biopsy samples has proved to be an invaluable resource for many translational studies by our group, as demonstrated in the literature [13,14]. An example of the successful use of the biobank is the study by Rajatapiti et al [13], which demonstrated that the expression of glucocorticoid, retinoid and thyroid hormone receptors is not altered in lungs of patients with CDH.…”

Section: Discussionmentioning

confidence: 99%

“…Our biobank of lung biopsy samples has proved to be an invaluable resource for many translational studies by our group, as demonstrated in the literature [13,14]. An example of the successful use of the biobank is the study by Rajatapiti et al [13], which demonstrated that the expression of glucocorticoid, retinoid and thyroid hormone receptors is not altered in lungs of patients with CDH. This is especially important in diseases such as CDH in which survival has improved (and therefore the opportunity to obtain material from deceased patients has become rare), but there is still a need for elucidating the exact pathogenetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…By increasing the amount of lung tissue available, we aspired to potentially obtain a better insight into the pathology of the lungs by performing a microscopic examination and to potentially facilitate translational research into the pathogenesis of CDH [13,14]. The main objective of this study was to evaluate our experience with minimally invasive postmortem lung biopsy as an alternative for obtaining postmortem tissue when full autopsy is refused in CDH patients.…”

Section: Introductionmentioning

confidence: 99%

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Postmortem Biopsy to Obtain Lung Tissue in Congenital Diaphragmatic Hernia

et al. 2013

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Background: The accrual of human tissues from autopsies for diagnostic and translational research has decreased significantly over the last decades. Objectives: The objective of this study was to evaluate our experience with lung biopsy through a minithoracotomy as an alternative for obtaining postmortem tissue when full autopsy is refused in congenital diaphragmatic hernia (CDH) patients. Methods: Within 2 h of death we routinely asked parents for permission to perform an autopsy. Starting in 2001, parents who refused autopsy were asked permission for a postmortem lung biopsy. Pathology autopsy and biopsy reports were compared to clinical records. Results: Between 2001 and 2009, 46 patients died from CDH. Permission for autopsy was granted in 5 patients (11%). Of the remaining 41 patients, the parents of 15 (33%) agreed to postmortem lung biopsy. In all cases, additional findings were reported from the autopsy or biopsy, without changing the originally reported cause of death. In 1 case, we isolated fibroblasts from the lung biopsy using standardized cell culture techniques. Parents were able to take their child home with a minimal delay following biopsy. Conclusions: Parents refusing a full autopsy frequently agree to postmortem organ biopsy. This approach should therefore be considered as a valuable alternative, when permission for full autopsy is declined, for obtaining human tissues for both diagnostic and research purposes and is potentially applicable to other anomalies.

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