title: Antioxidant Supplementation Modulates Age-Related Placental Bed Morphology and Reproductive Outcome in Mice.
abstract: The number of women who delay their first childbirth is increasing. This demographic shift is an important health issue because advanced maternal age is a risk factor for reproductive capacity loss and the occurrence of placental bed disorders that may lead to placenta abruption, preeclampsia, and placenta insufficiency. A redox imbalance status, resulting from the enhanced production of reactive oxygen species or their deficient neutralization, is proposed to occur in this setting. Thus, uterine redox status was evaluated in young (8- to 12-wk-old) and reproductively aged (38- to 42-wk-old) mice. In addition, it was hypothesized that specific dietary antioxidant supplementation would restore the balance and improve the reproductive outcome of aging female mice. To test this hypothesis, two different antioxidants, the nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor apocynin and the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL), were added to the drinking water of female mice prior to and during pregnancy. Compared to younger females, uteri from reproductively aged nonpregnant mice exhibited areas of endometrial cystic dilation, increased level of NOX1 expression, and enhanced protein carbonylation, especially in the apical surface of the luminal epithelium. Both antioxidants decreased protein carbonylation level in the uterus of reproductively aged mice. When reproductively aged females became pregnant, the litter size was smaller and fetuses were heavier. The change was accompanied by a significant decrease in decidua thickness. Provision of apocynin significantly increased litter size and restored decidua thickness. Reproductively aged mice provided with TEMPOL did not evidence such benefits, but whereas apocynin normalized fetal birth weight, TEMPOL further increased it. These findings emphasize that uterine redox balance is important for reproductive success and suggest that age-related redox imbalance might be compensated by specific antioxidant supplementation.
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Department of Experimental Biology, Faculty of Medicine of Porto University, Porto, Portugal esilva@med.up.pt.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Silva
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Department of Experimental Biology, Faculty of Medicine of Porto University, Porto, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Soares
authors.affiliation: Department of Experimental Biology, Faculty of Medicine of Porto University, Porto, Portugal.
authors.forename: Filipe
authors.initials: F
authors.lastname: Costa
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Department of Experimental Biology, Faculty of Medicine of Porto University, Porto, Portugal.
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Castro
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Department of Experimental Biology, Faculty of Medicine of Porto University, Porto, Portugal Faculty of Nutrition and Food Sciences of Porto University, Porto, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Matos
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal Department of Experimental Biology, Faculty of Medicine of Porto University, Porto, Portugal Obstetrics-Gynecology, Hospital-CUF Porto, Porto, Portugal.
authors.forename: Henrique
authors.initials: H
authors.lastname: Almeida
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003656:Decidua / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000033:anatomy & histology; D008098:Litter Size; D051379:Mice; D008810:Mice, Inbred C57BL; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D000074624:NADPH Oxidase 1; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010920:Placenta / Q000033:anatomy & histology* / Q000187:drug effects*; D011247:Pregnancy; D050050:Protein Carbonylation / Q000187:drug effects; D012098:Reproduction / Q000187:drug effects*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; C056165:acetovanillone; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C001803:tempol
keywords: TEMPOL; aging; apocynin; decidua; litter size; oxidative stress; pregnancy; superoxide dismutase