Intra-uterus phthalate exposure, ROS formation and altered mitochondrial D-loop methylation pattern at birth as potential triggers and markers of Alzheimer’s disease

Abstract

Alzheimer's Disease is one of the fastest growing causes of dementia, and the factors that trigger its pathology have not yet been completely unraveled. In addition, Alzheimer's disease (AD) impacts not only the individual affected, but also the familial and socio-economic spheres. On the other hand, phthalates are plasticizers capable of interfering with the endocrine system and which, due to the nature of the most varied objects, utensils and tools used by society, as well as the propensity of these chemicals to dissociate from their matrices and accumulate in the environment and living organisms, are frequently and in large quantities exposed to humans. This study explores a possible relationship between exposure to phthalates and the development of Alzheimer's pathophysiology, with emphasis on prenatal exposure and its influence on the risk of dementia in adulthood. Based on the literature consulted, mechanisms for the generation of oxidative stress in the nervous system by phthalates were described and it was proposed how this could be related to the triggering of Alzheimer's pathophysiology, primarily in view of the modification of the methylation pattern of mitochondrial DNA. In addition, it was observed that exposure to phthalates during intrauterine life is capable of generating changes in the epigenetic pattern at birth. An alternative for the early detection of mitochondrial metabolic dysfunctions, which could potentially evolve into dementia, could involve monitoring D-loop methylation levels. Therefore, we hypothesized that intrauterine exposure to phthalates may generate oxidative stress in the brain and alter the mtDNA methylation pattern, which can perturb mitochondrial function and increase risk of development of AD at adulthood. We suggest that these phthalate-induced metabolic changes may be detected by the D-loop methylation pattern at birth. We highlight the need for more research integrating the emerging fields of mitoepigenetics and bioenergetic medicine with neurodegenerative diseases, and an experimental design employing zebrafish as a model is suggested to test the hypotheses raised.