Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition

Kling, David E.; Cavicchio, Amanda J.; Sollinger, Christina; Schnitzer, Jay J.; Kinane, T. Bernard; Newburg, David S.

doi:10.1002/bdrb.20247

Cited by 16 publications

(6 citation statements)

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“…For example, mesenchyme-derived cells normally undergo apoptosis at the pseudoglandular stage (embryonic days 12 – 17); a time frame that corresponds with the studies herein [35–37, 45]. In addition, treatment of fetal rat lung explants with the MEK1/2 kinase inhibitor, U0126 or a teratogenic diphenyl ether, nitrofen induced high levels of mesenchymal but not epithelial apoptosis [26, 34]. Moreover, inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling with neutralizing antibodies induced high levels of apoptosis in human fetal lung mesenchyme but not epithelium [46].…”

Section: Discussionmentioning

confidence: 90%

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Group B Streptococcus induces a caspase-dependent apoptosis in fetal rat lung interstitium

Kling

Tsvang

Murphy

et al. 2013

Microbial Pathogenesis

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Group B Streptococcus (GBS) is an important pathogen and is associated with sepsis and meningitis in neonates and infants. An ex vivo model that facilitates observations of GBS interactions with multiple host cell types over time was used to study its pathogenicity. GBS infections were associated with profound reductions in fetal lung; explant size, and airway branching. Elevated levels of apoptosis subsequent to GBS infections were observed by whole-mount confocal immunofluorescence using activated-caspase-3-antibodies and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays. The caspase inhibitor Z-VAD-FMK abolished the increase in TUNEL-positive cells associated with GBS infections, indicating that the GBS-induced apoptosis was caspase-dependent. Digital image analyses revealed that both GBS and the active form of caspase-3 were distributed primarily within the lung interstitium, suggesting that these tissues are important targets for GBS. Antibodies to the active form of caspase-3 colocalized with both macrophage- and erythroblast-markers, suggesting that these hematopoietic cells are vulnerable to GBS-mediated pathogenesis. These studies suggest that GBS infections profoundly alter lung morphology and caspase-dependent hematopoietic cell apoptosis within the lung interstitium play roles in GBS pathophysiology in this model.

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Section: Discussionmentioning

confidence: 90%

“…Since other studies have suggested that different fetal lung cell types undergo apoptosis variably, the distribution of apoptotic cells within the explants was investigated [34–37]. The distribution of activated caspase-3 within the explant tissue beds was characterized by whole-mount immunofluorescence confocal microscopy as described above.…”

Section: Resultsmentioning

confidence: 99%

Group B Streptococcus induces a caspase-dependent apoptosis in fetal rat lung interstitium

Kling

Tsvang

Murphy

et al. 2013

Microbial Pathogenesis

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“…The nitrofen-induced CDH model is one of the most widely used animal models to study the pathogenesis of PH in CDH (9,13,15). However, the exact molecular mechanism underlying nitrofeninduced PH in this model is still not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Antenatal retinoic acid administration increases trophoblastic retinol-binding protein dependent retinol transport in the nitrofen model of congenital diaphragmatic hernia

et al. 2015

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Background: Low pulmonary retinol levels and disrupted retinoid signaling pathway (RSP) have been implicated in the pathogenesis of congenital diaphragmatic hernia (CDH) and associated pulmonary hypoplasia (PH). It has been demonstrated that nitrofen disturbs the main retinol-binding protein (RBP)-dependent trophoblastic retinol transport. Several studies have demonstrated that prenatal treatment with retinoic acid (RA) can reverse PH in the nitrofen-induced CDH model. We hypothesized that maternal administration of RA can increase trophoblastic RBP-dependent retinol transport in a nitrofen model of CDH. Methods: Pregnant rats were treated with nitrofen or vehicle on gestational day 9 (D9) and sacrificed on D21. RA was given i.p. on D18, D19, and D20. Retinol and RA levels were measured using high-performance liquid chromatography. Immunohistochemistry was performed to evaluate trophoblastic expression of RBP. Expression levels of the primary RSP genes were determined using quantitative real-time PCR and immunohistochemistry. results: Markedly increased trophoblastic RBP immunoreactivity was observed in CDH+RA compared to CDH. Significantly increased serum and pulmonary retinol and RA levels were detected in CDH+RA compared to CDH. Pulmonary expression of RSP genes and proteins were increased in CDH+RA compared to CDH. conclusion: Increased trophoblastic RBP expression and retinol transport after antenatal administration of RA suggest that retinol-triggered RSP activation may attenuate CDHassociated PH by elevating serum and pulmonary retinol levels. t he mortality rate of infants born with congenital diaphragmatic hernia (CDH) remains high despite prenatal diagnosis and improved postnatal treatment strategies (1). The high morbidity and mortality is mainly attributed to pulmonary hypoplasia (PH) and associated persistent pulmonary hypertension (2). Much of the current understanding of the pathogenesis of PH in CDH originates from experimental animal studies. Maternal exposure to nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) in rodents during midgestation results in a high rate of CDH and associated PH in their fetuses, which is strikingly similar to the human condition (3).It is well understood that retinoids-vitamin A and its derivatives-are essential for the morphogenesis of most developing organs and tissues, including the lungs (4). The placenta has a major role in retinol homeostasis in fetal life (5). As the fetus cannot synthesize retinol, it relies on circulating maternal retinol, which reaches the fetus by crossing the maternal-fetal barrier in the placenta (6). Although retinol-binding protein (RBP) is essential for retinol transport within the circulation (7), maternal RBP does not cross the placenta (8). Therefore, in order to enter the fetal circulation, maternal retinol bound to maternal RBP must be released at the maternal-fetal interface. Fetal RBP is produced by the trophoblast and then forms a complex with retinol to be subsequently released into the fetal circulation and delivered to the ...

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“…The copyright holder for this preprint (which this version posted April 4, 2020. ; https://doi.org/10.1101/2020.04.03.024851 doi: bioRxiv preprint 14 RA signaling is an important regulator of normal diaphragm development and when inhibited causes CDH (Clugston et al, 2010a). Pharmacological inhibition of RA synthesis via administration to pregnant females of nitrofen, a herbicide that inhibits ALDH1A2 (Alles et al, 1995;Mey et al, 2003;Kling et al, 2010), inhibits growth of the PPFs to ultimately cause CDH in embryos (Costlow and Manson, 1981;Nakao and Ueki, 1987). To test whether nitrofen similarly affects PPF proliferation in vitro, we cultured E12.5 PPFs in the presence of 100 µM nitrofen.…”

Section: Genetic and Pharmacological Manipulations That Lead To Cdh In Vivo Cause Decreased Ppf Proliferation In Vitromentioning

confidence: 99%

Cell culture system to assay candidate genes and molecular pathways implicated in congenital diaphragmatic hernias

Bogenschutz

Sefton

Kardon

2020

Developmental Biology

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Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition

Abstract: The observed declines in nitrofen-associated retinoic acid signaling appear to be independent of RALDH inhibition and likely result from nitrofen induced cell death/apoptosis. These results support a cellular apoptotic mechanism of CDH development, independent of RALDH inhibition.

Cited by 16 publications

References 57 publications

Group B Streptococcus induces a caspase-dependent apoptosis in fetal rat lung interstitium

Group B Streptococcus induces a caspase-dependent apoptosis in fetal rat lung interstitium

Antenatal retinoic acid administration increases trophoblastic retinol-binding protein dependent retinol transport in the nitrofen model of congenital diaphragmatic hernia

Cell culture system to assay candidate genes and molecular pathways implicated in congenital diaphragmatic hernias

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