Maternal nicotine exposure leads to decreased cardiac protein disulfide isomerase and impaired mitochondrial function in male rat offspring

Barra, Nicole G.; Lisyansky, Maria; VanDuzer, Taylor A; Raha, Sandeep; Holloway, Alison C.; Hardy, Daniel B.

doi:10.1002/jat.3503

Cited by 19 publications

(27 citation statements)

References 50 publications

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“…This suggests that in the absence of NGLY1, BMP4 is trapped in the ER. The anti-KDEL antibody used in our studies is raised against the KDEL-containing C-terminal part of the GRP78/BiP and can recognize this protein in immunoblots ( Cai et al, 1998 ; Barra et al, 2017 ). GRP78/Bip (official name: heat shock protein family A member 5, HSPA5) is a major ER luminal chaperone whose expression can be used to monitor ER stress ( Lee, 2005 ).…”

Section: Resultsmentioning

confidence: 99%

Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation

Galeone

Adams

Matsuda

et al. 2020

eLife

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During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzyme N-glycanase 1 (NGLY1) is proposed to remove N-glycans from misfolded N-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulates Drosophila BMP signaling in a tissue-specific manner (Galeone et al., 2017). Here, we establish the Drosophila Dpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress and prompts the ER recruitment of NGLY1. The ER-associated NGLY1 then deglycosylates misfolded BMP4 molecules to promote their retrotranslocation and proteasomal degradation, thereby allowing properly-folded BMP4 molecules to proceed through the secretory pathway and activate signaling in other cells. Our study redefines the role of NGLY1 during ERAD and suggests that impaired BMP4 signaling might underlie some of the NGLY1 deficiency patient phenotypes.

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Section: Resultsmentioning

confidence: 99%

Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation

Galeone

Adams

Matsuda

et al. 2020

eLife

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“…Mammalian lung morphogenesis is a complex, finely orchestrated program, which progresses through well defined, sequential stages to result in fully functional lung; for example, the rat lung development proceeds through the embryonic (E11-13), pseudoglandular (E13-18.5), canalicular (E18. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], saccular (E20-PND4), and alveolar (PND4-21) stages. Specific growth factors and signaling mechanisms regulate each stage and drive its progression to the next stage [54].…”

Section: Discussionmentioning

confidence: 99%

“…Considerable evidence supports that nicotine is the main harmful substance in cigarettes, which rapidly crosses the placenta and accumulates in the fetus in concentrations much higher than maternal serum concentrations [4]. Prenatal exposure to nicotine not only affects the survival and birth weight of infants [5,6], but also adversely affects many developing systems including but not limited to the nervous, circulatory, immune, and respiratory systems [7][8][9][10]. Its effects are especially pronounced on the developing lung [11], as it predisposes the exposed offspring to many chronic respiratory conditions such as asthma, emphysema, pulmonary fibrosis, and so forth.…”

Section: Introductionmentioning

confidence: 99%

Developmental Timing Determines the Protective Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Offspring Lung Phenotype

Dai

Jiang

Zhao

et al. 2020

BioMed Research International

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Introduction. Environmental exposure of the developing offspring to cigarette smoke or nicotine is an important predisposing factor for many chronic respiratory conditions, such as asthma, emphysema, pulmonary fibrosis, and so forth, in the exposed offspring. Studies showed that electroacupuncture (EA) applied to maternal “Zusanli” (ST36) acupoints during pregnancy and lactation protects against perinatal nicotine exposure- (PNE-) induced lung damage. However, the most effective time period, that is, prenatal vs. postnatal, to attain this effect has not been determined. Objective. To determine the most effective developmental timing of EA’s protective effect against PNE-induced lung phenotype in the exposed offspring. Methods. Pregnant rats were given (1) saline (“S” group); (2) nicotine (“N” group); (3) nicotine + EA, exclusively prenatally (“Pre-EA” group); (4) nicotine + EA, exclusively postnatally (“Post-EA,” group); and (5) nicotine + EA, administered both prenatally and postnatally (“Pre- and Post-EA” group). Nicotine was injected once daily (1 mg/kg, 100 μl) and EA was administered to bilateral ST36 acupoints once daily during the specified time-periods. At the end of the experimental periods, key hypothalamic pituitary adrenal (HPA) axis markers in pups and dams, and lung function, morphometry, and the central molecular markers of lung development in the offspring were determined. Results. After nicotine exposure, alveolar mean linear intercept (MLI) increased, but mean alveolar number (MAN) decreased and lung PPARγ level decreased, but glucocorticoid receptor (GR) and serum corticosterone (Cort) levels increased, in line with the known PNE-induced lung phenotype. In the nicotine exposed group, maternal hypothalamic corticotropin releasing hormone (CRH) level decreased, but pituitary adrenocorticotropic hormone (ACTH) and serum Cort levels increased. In the “Pre- and Post-EA” groups, PNE-induced alterations in lung morphometry, lung development markers, and HPA axis were blocked. In the “Pre-EA” group, PNE-induced changes in lung morphometry, GR, and maternal HPA axis improved; lung PPARγ and serum Cort levels were slightly but not significantly improved. In contrast, the exclusive “Post-EA” group showed none of these benefits. Conclusions. Maternal EA applied to ST36 acupoints during both pre- and postnatal periods preserves offspring lung structure and function despite perinatal exposure to nicotine. EA applied during the “prenatal period” affords only limited benefits, whereas EA applied during the “postnatal period” is ineffective, suggesting that the EA’s effects in modulating PNE-induced lung phenotype are limited to specific time-periods during lung development.

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“…After 24 h in culture, 15 µM Δ9-THC did not significantly alter the mtDNA expression of ND-1 (Fig. 5A), an indicator of total mitochondrial number [46,47]. However, Δ9-THC decreased citrate synthase protein levels by 25% ( Fig.…”

Section: δ9-thc Treatment Decreases the Expression Of Mitochondrial Cmentioning

confidence: 92%

Δ9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts

Lojpur

Easton

Raez-Villanueva

et al. 2019

Reproductive Toxicology

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While studies have demonstrated that the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC) alone induces placental insufficiency and fetal growth restriction, the underlying mechanisms remain elusive. Given that both (i) endoplasmic reticulum (ER) stress in pregnancy and (ii) gestational exposure to Δ9-THC leads to placental deficiency, we hypothesized that Δ9-THC may directly induce placental ER stress, influencing trophoblast gene expression and mitochondrial function. BeWo human trophoblast cells treated with Δ9-THC (3-30 μM) led to a dose-dependent increase in all ER stress markers and CHOP; these effects could be blocked with CB1R/CB2R antagonists. Moreover, expression of ER stress-sensitive genes ERRγ, VEGFA, and FLT-1 were increased by Δ9-THC, and abrogated with the ER stress inhibitor TUDCA. Δ9-THC also diminished mitochondrial respiration and ATP-coupling due to decreased abundance of mitochondrial chain complex proteins. Collectively, these findings indicate that Δ9-THC can directly augment ER stress resulting in aberrant placental gene expression and impaired mitochondrial function.

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Maternal nicotine exposure leads to decreased cardiac protein disulfide isomerase and impaired mitochondrial function in male rat offspring

Cited by 19 publications

References 50 publications

Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation

Regulation of BMP4/Dpp retrotranslocation and signaling by deglycosylation

Developmental Timing Determines the Protective Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Offspring Lung Phenotype

Δ9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts

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