Maternal diabetes promotes offspring lung dysfunction and inflammation in a sex-dependent manner

Abstract

Exposure to maternal diabetes is increasingly recognized as a risk factor for chronic respiratory disease in children. It is currently unclear, however, whether maternal diabetes affects the lung health of male and female offspring equally. This study characterizes the sex-specific impact of a murine model of diet-induced gestational diabetes (GDM) on offspring lung function and airway inflammation. Female adult mice are fed a high-fat (45% kcal) diet for 6-weeks prior to mating. Control offspring are from mothers fed a low fat (10% kcal) diet. Offspring were weaned and fed a chow diet until 10-weeks of age, at which point lung function was measured and lung lavage was collected. Male, but not female offspring exposed to GDM had increased lung compliance and reduced lung resistance at baseline. Female offspring exposed to GDM displayed increased methacholine reactivity and elevated levels of pro-inflammatory cytokines (e.g. interleukin (IL)-1β, IL-5, and CXCL1) in lung lavage. Female GDM offspring also displayed elevated abundance of matrix metalloproteinases (MMP) within their airways, namely MMP-3 and MMP-8. These results indicate disparate effects of maternal diabetes on lung health and airway inflammation of male and female offspring exposed to GDM. Female mice may be at greater risk of inflammatory lung conditions, such as asthma, while male offspring display changes that more closely align with models of chronic obstructive pulmonary disease. In conclusion, there are important sex-based differences in the impact of maternal diabetes on offspring lung health that could signal differences in future disease risk.

Maternal gestational diabetes mellitus and the childhood asthma in offspring: a meta-analysis

“…Currently, the mechanisms underlying the association between GDM and childhood asthma in offspring remain to be elucidated. A recent preclinical study in a murine model of diet-induced GDM showed that female offspring exposed to GDM displayed increased methacholine reactivity, elevated proinflammatory cytokines in lung lavage, and an elevated abundance of matrix metalloproteinases in their airway, which all subsequently expose them to an increased risk of inflammatory lung conditions, such as asthma [ 33 ]. However, these changes were not observed in male offspring exposed to GDM [ 33 ].…”

Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring

“…Higher bronchial alveolar lavage fluid cell count with an increased neutrophil percentage and elevated concentration of IL-6 was also observed in the same study suggesting that an activated pro-inflammatory state may play a role in reactive airway disease in children born to mothers with obesity. Another study found a female offspringspecific increase in methacholine reactivity, as well as elevated levels of pro-inflammatory cytokines (IL-1b, IL-5, and CXCL1), MMP-3 and MMP-8 in lung lavage (Pascoe et al, 2022). The exacerbated allergic response in offspring of obese mice was also observed in response to allergen (ovalbumin) challenge (RR et al, 2019).…”

Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia

“…Newborns and 3-week-old offspring of diabetic mothers had smaller lungs ( 128 ) and delayed maturation ( 129 ). Male O-GDM had increased lung compliance and reduced lung resistance at 10 weeks old, which may evolve into a chronic obstructive pulmonary disease ( 130 ). A high glucose environment was also demonstrated to activate the apoptosis of primary dental papilla cells and dental epithelial stem cells via nuclear factor κB (NF-κB) signaling pathway, resulting in impaired odontogenesis in maternal diabetic offspring mice ( 131 ).…”

“…Thus, the blastocyst development was impaired, the embryo implantation was inhibited, and the growth and development of the fetus during middle and late gestational periods were delayed ( 140 ). Systematic pro-inflammatory cytokines or local immune cells acted on islets ( 27 , 141 ), liver ( 35 ), peripheral adiposity ( 142 ), heart ( 75 , 143 , 144 ), kidney ( 80 ), brain ( 145 , 146 ), reproductive tract ( 140 ), lung ( 130 ), and microbiota ( 133 ), resulting in damage to organ function.…”