Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation,Molecular Metabolism

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Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation
Molecular Metabolism ( IF 8.1 ) Pub Date : 2020-10-05 , DOI: 10.1016/j.molmet.2020.101094
Colette N Miller ₁ , Janice A Dye ₂ , Andres R Henriquez ₃ , Erica J Stewart ₃ , Katelyn S Lavrich ₄ , Gleta K Carswell ₅ , Hongzu Ren ₂ , Danielle L Freeborn ₂ , Samantha J Snow ₂ , Mette C Schladweiler ₂ , Judy H Richards ₂ , Prasada R S Kodavanti ₂ , Anna Fisher ₂ , Brian N Chorley ₅ , Urmila P Kodavanti ₂

Affiliation

Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, 109 T.W. Alexander Dr., Mail Code: B105-02, Research Triangle Park, NC, 27711, USA; Oak Ridge Institute for Science and Education Research Participation Program, US Environmental Protection Agency, 109 T.W. Alexander Dr., Mail Code: B105-02, Research Triangle Park, NC, 27711, USA.
Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, 109 T.W. Alexander Dr., Mail Code: B105-02, Research Triangle Park, NC, 27711, USA.
Oak Ridge Institute for Science and Education Research Participation Program, US Environmental Protection Agency, 109 T.W. Alexander Dr., Mail Code: B105-02, Research Triangle Park, NC, 27711, USA.
Division of the National Toxicology Program, National Institute of Environmental Health Sciences, 530 Davis Dr., Keystone Building, Durham, NC, 27713, USA.
Biomolecular and Computational Toxicology Division, Center for Computational Toxicology and Exposure, Office of Research and Development, US Environmental Protection Agency, 109 T.W. Alexander Dr., Mail Code: B105-02, Research Triangle Park, NC, 27711, USA.

Objective

The importance of the placenta in mediating the pre- and post-natal consequences of fetal growth restriction has been increasingly recognized. However, the influence of placental sexual dimorphism on driving these outcomes has received little attention. The purpose of this study was to characterize how sex contributes to the relationship between placental metabolism and fetal programming utilizing a novel rodent model of growth restriction.

Methods

Fetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone (4 h/day) during implantation receptivity (gestation days [GDs] 5 and 6) in Long-Evans rats. Control rats were exposed to filtered air. At GD 21, placental and fetal tissues were obtained for metabolic and genomic assessments.

Results

Growth-restricted male placentae exhibited increased mitochondrial biogenesis, increased oxygen consumption, and reduced nutrient storage. Male growth-restricted fetuses also had evidence of reduced adiposity and downregulation of hepatic metabolic signaling. In contrast, placentae from growth-restricted females had elevated markers of autophagy accompanied by an observed protection against hepatic metabolic perturbations. Despite this, growth restriction in females induced a greater number of hypothalamic gene and pathway alterations compared to growth-restricted males.

Conclusions

Increases in mitochondrial metabolism in growth-restricted male placentae likely initiates a sequela of adaptations that promote poor nutrient availability and adiposity. Divergently, the female placenta expresses protective mechanisms that may serve to increase nutrient availability to support fetal metabolic development. Collectively, this work emphasizes the importance of sex in mediating alterations in placental metabolism and fetal programming.

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