Abstract
The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring's life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes presented increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in females. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.
Original language | English |
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Article number | 155793 |
Journal | Metabolism: Clinical and Experimental |
Volume | 153 |
DOIs | |
State | Published - Apr 2024 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2024
Funding
This study was supported by the Swiss National Science Foundation via the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland (grant no. 51NF40-185544 ), the Swiss 3R Competence Centre (3RCC; grant no OC-2019-019 ), and the Lindenhof Foundation , Bern, Switzerland (grant no. 17-15-F ).
Funders | Funder number |
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Lindenhof Foundation | 17-15-F |
Swiss 3R Competence Centre | OC-2019-019 |
University of Bern | 51NF40-185544 |
nccr – on the move | |
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung |
Keywords
- Environmental stress
- Fetal programming
- Metabolic disease
- Miscarriage
- Placenta
- Preeclampsia
- Sex differences