Reproductive Toxicology 77 (2018) 33–42 Contents lists available at ScienceDirect Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox The effect of oxidative stress induced by tert-butylhydroperoxide under distinct folic acid conditions: An in vitro study using cultured human trophoblast-derived cells Jaqueline Vieira Carletti a , Ana Correia-Branco b,c , Claudia Raquel Silva b , Nelson Andrade b , Lenir Orlandi Pereira Silva a , Fátima Martel b,c,∗ a Programa de Pós-Graduac¸ ão em Neurociências, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, sala 107, 90050-170, Porto Alegre, RS, Brazil b Unidade de Bioquímica - Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal c Instituto de Investigac¸ ão e Inovac¸ ão em Saúde, Universidade do Porto, Portugal a r t i c l e i n f o Article history: Received 24 October 2017 Received in revised form 2 February 2018 Accepted 5 February 2018 Available online 6 February 2018 Keywords: Folate Preeclampsia Placenta Oxidative stress a b s t r a c t Preeclampsia is a pregnancy disorder characterized by high maternal blood pressure, fetal growth restric- tion and intrauterine hypoxia. Folic acid is a vitamin required during pregnancy. In this work, we investigated the relationship between preeclampsia and the intake of distinct doses of folic acid dur- ing pregnancy. Considering that preeclampsia is associated with increased placental oxidative stress levels, we investigated the effect of oxidative stress induced by tert-butylhydroperoxide (TBH) in human trophoblast-derived cells cultured upon deficient/low, physiological and supra-physiological folic acid levels. The negative effect of TBH upon thiobarbituric acid reactive substances (TBARS), total, reduced and oxidized glutathione, cell viability, cell proliferation, culture growth and cell migration was more marked under folic acid excess. This study suggests more attention on the dose administered, and ultimately, on the overall folic acid levels during pregnancy, in the context of preeclampsia risk. © 2018 Elsevier Inc. All rights reserved. 1. Introduction Preeclampsia is a pregnancy disorder characterized by high maternal blood pressure and proteinuria at ≥20 weeks of gesta- tion [1,2]. Preeclampsia remains an important cause of maternal and fetal morbidity and mortality, affecting 1–8% of all pregnan- cies [3–5]. In severe cases, preeclampsia complications may include maternal seizures, cerebrovascular accident, thrombocytopenia, renal failure, fetal growth restriction, intrauterine hypoxia, prema- turity and death [2,6–9]. The placenta, a materno-fetal complex organ formed during pregnancy, is responsible for nutrient transport, gas exchange, hor- mone synthesis and embryo protection [10,11]. An inadequate placentation process, including inadequate trophoblast invasion and insufficient remodeling of the uterine spiral artery, results ∗ Corresponding author at: Unidade de Bioquímica - Departamento de Biomedic- ina, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. E-mail address: fmartel@med.up.pt (F. Martel). in persistent placental hypoxia/ischemia. This in turn results in an imbalance in the production of pro-angiogenic/anti-angiogenic factors into the maternal circulation [2,3,6]. Although the patho- physiology of preeclampsia remains unclear, this imbalance in favor of anti-angiogenic factors appears to be associated with the onset of maternal endothelial dysfunction, affecting all maternal organ systems [2,12]. Also, an increased oxidative stress imbal- ance has been described during the pathogenesis and progression of preeclampsia, leading to fetal programming of deleterious effects such as cardiovascular complications and metabolic syndrome in adulthood [13–16]. Folic acid is the synthetic form of folate, a member of B 9 vitamin family, which is essential for the biosynthesis of nucleotides, amino acids and S-adenosyl-l-methionine [17,18]. It is well established that an adequate intake of folic acid is required for the correct devel- opment of neural tube and central nervous system and the growth of placenta and fetus [19–21]. Accordingly, supplementation with folic acid (0.4 mg/day) has been recommended to all women within childbearing age from the beginning of pregnancy and until the end of the first trimester of pregnancy, while 4–5 mg/day is advised for women at high risk of neural tube disease [22,23]. https://doi.org/10.1016/j.reprotox.2018.02.003 0890-6238/© 2018 Elsevier Inc. All rights reserved.