Clemente, Diana B PCasas, MaribelVilahur, NadiaBegiristain, HaizeaBustamante, MarionaCarsin, Anne-ElieFernández, Mariana FFierens, FransGyselaers, WilfriedIñiguez, CarmenJanssen, Bram GLefebvre, WouterLlop, SabrinaOlea, NicolásPedersen, MariePieters, NickySanta Marina, LoretoSouto, AnaTardón, AdoninaVanpoucke, CharlotteVrijheid, MartineSunyer, JordiNawrot, Tim S2016-12-022016-12-022016-05Clemente DB, Casas M, Vilahur N, Begiristain H, Bustamante M, Carsin AE, et al. Prenatal Ambient Air Pollution, Placental Mitochondrial DNA Content, and Birth Weight in the INMA (Spain) and ENVIRONAGE (Belgium) Birth Cohorts. Environ. Health Perspect. 2016; 124(5):659-650091-6765http://hdl.handle.net/10668/2555Journal Article;BACKGROUND Mitochondria are sensitive to environmental toxicants due to their lack of repair capacity. Changes in mitochondrial DNA (mtDNA) content may represent a biologically relevant intermediate outcome in mechanisms linking air pollution and fetal growth restriction. OBJECTIVE We investigated whether placental mtDNA content is a possible mediator of the association between prenatal nitrogen dioxide (NO2) exposure and birth weight. METHODS We used data from two independent European cohorts: INMA (n = 376; Spain) and ENVIRONAGE (n = 550; Belgium). Relative placental mtDNA content was determined as the ratio of two mitochondrial genes (MT-ND1 and MTF3212/R3319) to two control genes (RPLP0 and ACTB). Effect estimates for individual cohorts and the pooled data set were calculated using multiple linear regression and mixed models. We also performed a mediation analysis. RESULTS Pooled estimates indicated that a 10-μg/m3 increment in average NO2 exposure during pregnancy was associated with a 4.9% decrease in placental mtDNA content (95% CI: -9.3, -0.3%) and a 48-g decrease (95% CI: -87, -9 g) in birth weight. However, the association with birth weight was significant for INMA (-66 g; 95% CI: -111, -23 g) but not for ENVIRONAGE (-20 g; 95% CI: -101, 62 g). Placental mtDNA content was associated with significantly higher mean birth weight (pooled analysis, interquartile range increase: 140 g; 95% CI: 43, 237 g). Mediation analysis estimates, which were derived for the INMA cohort only, suggested that 10% (95% CI: 6.6, 13.0 g) of the association between prenatal NO2 and birth weight was mediated by changes in placental mtDNA content. CONCLUSION Our results suggest that mtDNA content can be one of the potential mediators of the association between prenatal air pollution exposure and birth weight. CITATION Clemente DB, Casas M, Vilahur N, Begiristain H, Bustamante M, Carsin AE, Fernández MF, Fierens F, Gyselaers W, Iñiguez C, Janssen BG, Lefebvre W, Llop S, Olea N, Pedersen M, Pieters N, Santa Marina L, Souto A, Tardón A, Vanpoucke C, Vrijheid M, Sunyer J, Nawrot TS. 2016. Prenatal ambient air pollution, placental mitochondrial DNA content, and birth weight in the INMA (Spain) and ENVIRONAGE (Belgium) birth cohorts. Environ Health Perspect 124:659-665; http://dx.doi.org/10.1289/ehp.1408981.enContaminación del aireBélgicaPeso al nacerADN mitocondrialFemeninoDesarrollo fetalRetardo del crecimiento fetalGenes mitocondrialesModelos LinealesMitocondriasDióxido de nitrógenoPlacentaEmbarazoEspañaMedical Subject Headings::Health Care::Environment and Public Health::Public Health::Environmental Pollution::Air PollutionMedical Subject Headings::Geographicals::Geographic Locations::Europe::BelgiumMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Size::Body Weight::Birth WeightMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::DNA::DNA, Circular::DNA, MitochondrialMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Morphogenesis::Embryonic and Fetal Development::Fetal DevelopmentMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Growth Disorders::Fetal Growth RetardationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, MitochondrialMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Linear ModelsMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::MitochondriaMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Gases::Nitrogen Oxides::Nitrogen DioxideMedical Subject Headings::Anatomy::Embryonic Structures::PlacentaMedical Subject Headings::Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Reproductive Physiological Processes::Reproduction::PregnancyMedical Subject Headings::Geographicals::Geographic Locations::Europe::Spainresearch article26317635open access10.1289/ehp.14089811552-9924PMC4858384