In utero exposure to xenoestrogens, associated health outcomes and epigenetic mechanisms in children

The prenatal period is a stage of special sensitivity to the adverse effects of environmental agents for the developing fetus. The human placenta is an organ that, in the interface between mother and fetus, plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent disease vulnerability in adulthood. There is increasing epidemiological evidence linking prenatal exposure to endocrine disrupting chemicals (EDCs) and adverse health outcomes in children, although mechanisms remain still unclear. Xenoestrogens are a group of endocrine disrupting chemicals that target the estrogenic signaling pathway and include a large number of compounds, both man-made and of natural origin, ubiquitously present in the environment, often at low doses. Xenoestrogen exposure has been related both in humans and in animal models to adverse health endpoints, most especially obesity and metabolic disorders, reproductive problems, increased risk for several types of cancers and neurobehavioral abnormalities. Prenatal epigenetic dysregulation has been proposed as a possible causal mechanism. The main objective of this thesis has been to evaluate the effects of prenatal exposure to mixtures of xenoestrogens on growth related and neuropsychological outcomes in children from the prospective Spanish birth cohort study INMA, INfancia y Medio Ambiente (Childhood and the Environment) Project, and to analyze whether in utero exposure to mixtures produces changes in placental DNA methylation, both globally or at specific genes and/or nearby regions. For that purpose, the Total Effective Xenoestrogen Burden (TEXB-alpha), a biomarker of the cumulative exposure to xenoestrogens, was measured in placental tissue using the E-Screen biossay. Information on birth outcomes was recorded by pediatricians or nurses at birth and at following time points, and neuropsychological assessment was conducted by trained psychologists using two different scales when children were around 2 and 4 years of age. DNA ...