In the past 37 years, assisted reproductive technologies (ART) have helped millions of couples worldwide to become parents. Despite their broad use, there is still uncertainty about their safety. It was soon observed that children born after ART have lower birthweight and more recently there is evidence that they have cardiometabolic abnormalities. Much research has been devoted tounderstanding these observations, mainly focussing on the search for epigenetic changes, but the question why these children are different still remains open.
In MitoART, we hypothesize that the low-birth weight and the cardiometabolic differences seen in ART children is due to an increased mitochondrial DNA (mtDNA) mutation load at conception, during gestation, and later in life, which in turn results in mitochondrial dysfunction. I propose that there are two non-mutually exclusive sources for these mutations. The first hypothesis is that some forms of female infertility are linked to an increased mtDNA mutation load, which can be transmitted to the offspring. Secondly, we propose that controlled ovarian stimulation, a procedure used in the majority of ART treatments, leads to mtDNA mutation in the oocytes.
In this project we will test if there are differences in the mtDNA mutation load between individuals conceived after ART or by spontaneous conception at different stages of their development. We will first develop a novel massive parallel sequencing-based approach to simultaneously screen the mtDNA for very low frequency point mutations and rearrangements both in DNA samples and single cells. We will screen material of different origins, all of them unique and precious, and carefully selected to answer the questions of the study. These include DNA samples of ART patients and controls, oocytes obtained in different conditions, placental samples, newborns, 14-year old children and 18-year olds.