The Woolcock Institute of Medical Research

Lung disease doesn’t affect everyone the same way — and a new study from researchers in the Woolcock’s Epigenetics of Chronic Disease research group suggests some of those differences are built into lung biology itself, long before illness appears. The paper, recently published in the FASEB (Federation of American Societies for Experimental Biology) Journal, adds molecular detail to long-observed sex differences in respiratory health.

The team set out to answer a deceptively simple question: are male and female lungs functionally different at a molecular level under healthy conditions? While clinical patterns in asthma and other respiratory diseases have long shown sex differences, the underlying baseline biology has been harder to pin down. This new work moves the field closer to that foundation.

The researchers examined bronchial responsiveness – how strongly the airways constrict when exposed to an inhaled trigger – in mice. They used methacholine, a standard testing agent in respiratory research, and found that male airways constricted more strongly than female airways. That confirmed a known physiological pattern — but the deeper insight came from what followed.

A GENETIC NETWORK

The group paired lung function testing with whole-lung RNA sequencing and gene co-expression network analysis. Rather than searching for a single “sex difference gene,” they mapped coordinated gene activity across thousands of genes at once. The result was a set of distinct gene network modules associated with airway responsiveness — and those modules differed by sex.

“Biological sex fundamentally shapes how the lungs function, even under healthy, non-diseased conditions,” said lead author Dr Razia Zakarya. “Male lungs are intrinsically more reactive to inhaled triggers than female lungs.” Importantly, she notes this effect arises from coordinated gene network behaviour rather than from one gene or one hormone pathway.

Many of the sex-linked networks were enriched for immune signalling, mitochondrial and metabolic activity and RNA regulation — systems that directly influence how airway cells respond to stress and constriction signals. This systems-level pattern suggests that baseline lung responsiveness is organised differently in males and females at multiple regulatory layers.

NOT JUST CHROMOSOMES

The researchers also tested whether early-life environment modifies these patterns. Some mother mice were exposed to fine particulate air pollution before and during pregnancy and nursing. That exposure did not change airway responsiveness by itself in adult offspring. However, it did change which gene networks were linked to responsiveness — and it did so differently in males and females. This indicates that developmental exposures may rewire lung molecular networks in a sex-dependent manner, even when outward physiology appears unchanged.

Notably, most of the genes driving these differences were not located on sex chromosomes. Instead, they sit across the broader genome, implying that sex-linked regulatory effects propagate widely through gene networks.

For respiratory and biomedical research, the message is clear: sex differences are not just clinical observations — they are embedded in baseline molecular architecture. Accounting for sex from the earliest stages of experimental design may therefore improve how risk, prevention, and treatment strategies are developed.

The paper “Sex and the developmental environment shape molecular networks underlying bronchial responsiveness in mice” by Razia Zakarya, Baoming Wang, Yik Lung Chan, Dikaia Xenaki, Kin Fai Ho, Hai Guo, Hui Chen, Brian G Oliver and Christopher O’Neill is published in the FASEB journal.

Find out more

• Our Epigenetics of Chronic Disease research group