Early Life Exposures and Milk Composition Affect Offspring Health
El Habbal, Noura
2022
Abstract
The Developmental Origins of Health and Disease (DOHaD) theory describes how early life exposures impact offspring disease risk and health outcomes. Common early life exposures include maternal stress and obesity. Additionally, early life nutrition during lactation can affect offspring health. This work focuses on understanding the mechanisms that impact offspring health by examining fetal and lactational physiology using mouse models and clinical data. Women who are subjected to chronic psychosocial stress and institutional racism have an increased risk of preterm delivery and infant morbidity and mortality. This is due to increased circulating levels of glucocorticoids, stress-induced steroid hormones. To understand the role of maternal elevated glucocorticoid levels on fetal and infant health, mice were exposed to the synthetic glucocorticoid, dexamethasone, during pregnancy. Mice treated with dexamethasone during gestation delivered reduced litter size and smaller offspring that were not viable postnatally. Hence, further studies were conducted to assess the role of the placental glucocorticoid receptor in mediating fetal growth restriction. A novel Cre-driven tissue-specific knockout of the placental glucocorticoid receptor was developed. Dexamethasone exposure during pregnancy caused fetal resorptions on embryonic day 14 in females only, but this was reversed by the placental glucocorticoid-receptor knockout. Furthermore, maternal dexamethasone exposure significantly reduced male placental and fetal weights on embryonic day 14, and this effect was not rescued by the placental glucocorticoid-receptor knockout. These findings provide new information about the role of placental glucocorticoid receptor in fetal development in a sex-specific manner. As maternal obesity is on the rise, it was important to assess the role of excess nutrient-sensing on lactational ability and milk composition. To better understand the effects of maternal obesity on early life nutrition, a mouse model of maternal adipose-specific Tsc1 knockout predicted to hyperactivate the mechanistic target of rapamycin 1 (mTORC1) was used. This model revealed that the knockout dams had higher milk fat percentage compared to the wild-type dams. This contributed to higher milk caloric concentration and heavier offspring weight during lactation. Additionally, milk of knockout dams had a lower percentage of saturated fatty acids and a higher percentage of monounsaturated fatty acids and the omega-3 fatty acid, docosahexaenoic acid. Together, these results highlight a novel role of adipocyte mTORC1 in controlling lipid secretion during lactation and support the importance of adipose function physiology on milk composition. To better understand the role of milk lipids on infant adiposity using clinical data, an exploratory analysis was performed to assess the relationship between the lipidomic profile of milk samples at two weeks and two months postpartum and infant adiposity. These results showed that several fatty acids were significantly correlated with infant weight-for-length z-scores, including positive correlations with vaccenic acid and negative correlations with docosahexaenoic acid. Dynamic changes in human milk lipids can have an impact on infant growth and allow us to better assess adiposity risk and develop interventions to reduce the risk of offspring morbidity and mortality. This work shows that elevated maternal glucocorticoids and nutrient excess affect early life development and offspring health outcomes. Additionally, clinical examination of human breast milk fatty acids highlights the role of milk composition in affecting infant adiposity. Future work is warranted to fully elucidate the mechanisms by which maternal stress, excess nutrient sensing, and milk composition affect offspring health. These findings can be used to improve interventions to improve offspring health.Deep Blue DOI
Subjects
Glucocorticoids, Maternal Stress, Placenta, Mammary Gland Physiology, Lactation, Infant Adiposity
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