Maternal Diabetes Influences Sensitivity to Cigarette Smoke Induced Lung Inflammation and Gene Expression in Offspring
Bibliographic record
Abstract
Abstract Introduction: COPD is a significant global health concern, with smoking as the primary cause. However, <20% of smokers develop COPD, suggesting there are additional factors that may modify sensitivity to cigarette smoke (CS), specifically, early-life exposures. Previously, we found that exposure to maternal diabetes (MD) modulates offspring response to acute CS, increasing airway resistance and B-cell infiltration in males. We now expand on this finding by measuring how MD alters offspring response to CS-induced changes in inflammatory mediators, and DNA methylation (DNAm) and abundance of mRNA related to lung growth/repair and CS detoxification. Methods: Six-week-old C57BL/6NJ female mice were fed with a high-fat diet (HF-45% kcal) or low-fat (control-10% kcal) control diet for 6-weeks, and throughout pregnancy and weaning. Diabetes during pregnancy was confirmed by glucose tolerance testing. Weaned offspring were fed with standard research chow-diet until 8-weeks of age, where they were exposed to CS/Room air (RA) for 50 mins, twice/day, for four days. Outcomes were measured 24 hrs after the last CS exposure. Serum Amyloid A (SAA) and Myeloperoxidase (MPO) were measured with ELISAs in the lung lavage. Lung tissues were assessed for MPO abundance, DNAm (pyrosequencing) and mRNA abundance (qPCR). Data analyzed by two-way ANOVA. Results: The abundance of mRNA involved in CS metabolism and lung growth were altered in MD offspring exposed to CS without specific changes in DNA methylation at target CpGs. Insulin-like growth factor binding protein-3 (IGFBP3) abundance in male MD-RA offspring was reduced, independent of CS exposure, compared to control males (-1.4-fold decrease). A similar decrease was seen in control-CS animals (-1.5-fold decrease). CS exposure significantly increased cytochrome p450 1A1 (CYP1A1) abundance in both sexes, regardless of diet, however the magnitude of the induction was smaller in male MD offspring (6.1- vs. 3.0-fold increase in control-CS vs MD-CS exposed respectively). Female MD-CS offspring had a significant induction of epoxide hydrolase (EPHX1) abundance (1.4-fold increase). Inflammatory marker SAA was elevated in male MD-CS offspring lavage (0.27±0.01 µg/mL) compared to control-CS (0.19±0.02 µg/mL). There were no differences in MPO concentration in the lavage, but lung tissue MPO abundance was significantly higher in MD-CS offspring compared to controls, regardless of sex (345.6±16.4 vs. 308.0±12.3 pg/mg of tissue). Conclusions: Exposure to MD alters offspring susceptibility towards CS-induced lung inflammation and changes the abundance of genes involved in lung growth and CS detoxification. These changes may influence individual susceptibility to CS induced lung damage.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".