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Item Correction: Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age(Springer Nature, 2024-04-25) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of MedicineCorrection to: Clinical Epigenetics (2024) 16:35 10.1186/s13148-024-01644-8 Following publication of the original article [1], the authors noticed that the NCBI Gene Expression Omnibus (GEO) accession series has been incorrectly listed as GSE253158 within the “Availability of data and materials section”. The correct GEO series for this work is GSE252169.Item Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging(Wiley, 2017-03-01) Davis, Hannah M.; Pacheco-Costa, Rafael; Atkinson, Emily G.; Brun, Lucas R.; Gortazar, Arancha R.; Harris, Julia; Hiasa, Masahiro; Bolarinwa, Surajudeen A.; Yoneda, Toshiyuki; Ivan, Mircea; Bruzzaniti, Angela; Bellido, Teresita; Plotkin, Lilian I.; Department of Anatomy & Cell Biology, IU School of MedicineSkeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.Item Effect of Vitamin C Supplementation for Pregnant Smokers on Offspring Airway Function and Wheeze at Age 5 Years: Follow-up of a Randomized Clinical Trial(American Medical Association, 2023) McEvoy, Cindy T.; Shorey-Kendrick, Lyndsey E.; Milner, Kristin; Harris, Julia; Vuylsteke, Brittany; Cunningham, Michelle; Tiller, Christina; Stewart, Jaclene; Schilling, Diane; Brownsberger, Julie; Titus, Hope; MacDonald, Kelvin D.; Gonzales, David; Vu, Annette; Park, Byung S.; Spindel, Eliot R.; Morris, Cynthia D.; Tepper, Robert S.; Pediatrics, School of MedicineImportance: Vitamin C supplementation (500 mg/d) for pregnant smokers has been reported to increase offspring airway function as measured by forced expiratory flow (FEF) through age 12 months; however, its effects on airway function at age 5 years remain to be assessed. Objective: To assess whether vitamin C supplementation in pregnant smokers is associated with increased and/or improved airway function in their offspring at age 5 years and whether vitamin C decreases the occurrence of wheeze. Design, setting, and participants: This study followed up the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) double-blind, placebo-controlled randomized clinical trial conducted at 3 centers in the US (in Oregon, Washington, and Indiana) between 2012 and 2016. Investigators and participants remain unaware of the treatment assignments. Forced expiratory flow measurements at age 5 years were completed from 2018 to 2021. Interventions: Pregnant smokers were randomized to vitamin C (500 mg/d) or placebo treatment. Main outcomes and measures: The primary outcome was the prespecified measurement of FEF between 25% and 75% expired volume (FEF25-75) by spirometry at age 5 years. Secondary outcomes included FEF measurements at 50% and 75% of expiration (FEF50 and FEF75), forced expiratory volume in 1 second (FEV1), and occurrence of wheeze. Results: Of the 251 pregnant smokers included in this study, 125 (49.8%) were randomized to vitamin C and 126 (50.2%) were randomized to placebo. Of 213 children from the VCSIP trial who were reconsented into this follow-up study, 192 (90.1%) had successful FEF measurements at age 5 years; 212 (99.5%) were included in the analysis of wheeze. Analysis of covariance demonstrated that offspring of pregnant smokers allocated to vitamin C compared with placebo had 17.2% significantly higher mean (SE) measurements of FEF25-75 at age 5 years (1.45 [0.04] vs 1.24 [0.04] L/s; adjusted mean difference, 0.21 [95% CI, 0.13-0.30]; P < .001). Mean (SE) measurements were also significantly increased by 14.1% for FEF50 (1.59 [0.04] vs 1.39 [0.04] L/s; adjusted mean difference, 0.20 [95% CI, 0.11-0.30]; P < .001), 25.9% for FEF75 (0.79 [0.02] vs 0.63 [0.02] L/s; 0.16 [95% CI, 0.11-0.22]; P < .001), and 4.4% for FEV1 (1.13 [0.02] vs 1.09 [0.02] L; 0.05 [95% CI, 0.01-0.09]; P = .02). In addition, offspring of pregnant smokers randomized to vitamin C had significantly decreased wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003). Conclusions and relevance: In this follow-up study of offspring of pregnant smokers randomized to vitamin C vs placebo, vitamin C supplementation during pregnancy resulted in significantly increased airway function of offspring at age 5 years and significantly decreased the occurrence of wheeze. These findings suggest that vitamin C supplementation for pregnant smokers may decrease the effects of smoking in pregnancy on childhood airway function and respiratory health.Item Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age(Springer Nature, 2024-02-27) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of MedicineBackground: We previously reported in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze. Methods: We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF25-75. We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age. Results: Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF25-75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment. Conclusions: Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci.Item Oral Vitamin C (500 mg/d) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP). A Randomized Trial(American Thoracic Society, 2019-05-01) McEvoy, Cindy T.; Shorey-Kendrick, Lyndsey E.; Milner, Kristin; Schilling, Diane; Tiller, Christina; Vuylsteke, Brittany; Scherman, Ashley; Jackson, Keith; Haas, David M.; Harris, Julia; Schuff, Robert; Park, Byung S.; Vu, Annette; Kraemer, Dale F.; Mitchell, Julie; Metz, Jill; Gonzales, David; Bunten, Carol; Spindel, Eliot R.; Tepp, Robert S.; Morris, Cynthia D.; Pediatrics, School of MedicineRationale: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. Objectives: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. Methods: A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. Measurements and Main Results: The primary outcome was FEF75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF50 and FEF25-75 obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C (n = 113) had the following FEFs at 3 months of age compared with those randomized to placebo (n = 109) as measured by FEF75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P = 0.10), FEF50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P = 0.02), and FEF25-75 (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34; P = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Conclusions: Although the primary outcome of FEF75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF50 and FEF25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF50 and FEF25-75) at 3 months of age in infants after vitamin C supplementation to pregnant smokers.Item Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12 Months of Age: A Randomized Trial(European Respiratory Society, 2020) McEvoy, Cindy T.; Shorey-Kendrick, Lyndsey E.; Milner, Kristin; Schilling, Diane; Tiller, Christina; Vuylsteke, Brittany; Scherman, Ashley; Jackson, Keith; Haas, David M.; Harris, Julia; Park, Byung S.; Vu, Annette; Kraemer, Dale F.; Gonzales, David; Bunten, Carol; Spindel, Eliot R.; Morris, Cynthia D.; Tepper, Robert S.; Pediatrics, School of MedicineBackground: Vitamin C (500 mg·day-1) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported. Objective: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age. Methods: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day-1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance. Results: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec-1 for FEF75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec-1 for FEF50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec-1 for FEF25-75 (95% CI, 9.7 to 100.5; p=0.013). Conclusions: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway.