Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Developmental air pollution exposure reprograms sex-specific molecular responses to physiological airway challenge in adult offspring (143392)

Razia Zakarya 1 2 , Baoming Wang 2 3 , Yik L Chan 2 , Dikaia Xenaki 3 , Kin F Ho 4 , Hai Guo 5 , Hui Chen 2 , Brian G. G. Oliver 2 3 , Christopher O'Neill 1 2
  1. Epigenetics of Chronic Disease Group, Woolcock Institute of Medical Research, Macquarie Park, NSW
  2. University of Technology Sydney, Broadway, NSW, Australia
  3. Respiratory Cell and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie Park, NSW, Australia
  4. Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong , SAR, People's Republic of China
  5. Air Quality Studies, Department of Civil and Environmental Engineering, The Hong Kong Polytechnic University, Hong Kong, SAR, The People's Republic of China

Background

Biological sex influences physiology, while maternal environment programs offspring development and lifelong health. Building on our previous demonstration of developmental programming in disease[1], we investigated whether developmental exposures also alter molecular networks underpinning normal physiological responses. We hypothesised that developmental exposure to maternal air pollution particulate matter (PM2.5) reprograms the transcriptional networks recruited during airway challenge, with biological sex further modifying these molecular responses.

Methods

Female BALB/c mice were exposed to PM2.5 or sham (saline) before mating and throughout gestation and lactation. Bronchial responsiveness (BR) to increasing methacholine doses was measured in 13-week-old offspring using FlexiVent (female sham n=11, female PM2.5 n=13, male sham n=11, male PM2.5 n=14). Lung RNA sequencing was performed on the same animals. Cellular deconvolution (CIBERSORTx) confirmed no differences in lung cellular composition between groups. Differential expression, weighted gene co-expression network and pathway enrichment analyses identified molecular pathways associated with sex, maternal exposure and BR.

Results

Maternal PM2.5 exposure did not alter bronchial responsiveness, allowing developmental programming to be examined in the absence of a physiological phenotype. Male offspring exhibited greater bronchial responsiveness than females (p<0.001). Differential expression identified 67 sex-associated genes enriched for immune, complement, metabolic and membrane-associated functions. Although maternal exposure did not alter physiological responses, it significantly changed gene co-expression modules associated with BR in a sex-dependent manner. These modules were enriched for immune receptor signalling, mitochondrial redox metabolism and RNA-binding pathways, demonstrating that developmental exposure reprogrammed the molecular architecture underlying airway responsiveness despite minimal physiological change.

Conclusion

Developmental exposure to maternal air pollution alters the molecular networks utilised by offspring to respond to physiological challenge without substantially altering physiology. These findings demonstrate that developmental programming can remodel the molecular architecture underpinning normal physiology without producing an overt phenotype, suggestive of deep canalisation of these responses in the face of exogenous stresses.

  1. Zakarya R, Chan YL, Wang B, et al. Developmental air pollution exposure augments airway hyperreactivity, alters transcriptome, and DNA methylation in female adult progeny. Commun Biol. 2025;8(1):400. Published 2025 Mar 8. doi:10.1038/s42003-025-07835-0