Placental secretome effects on reprogramming prenatal neuronal development and life-long function under environmental stress condition
Description
The “developmental origins of health and disease” (DOHaD) paradigm suggests that maternal diet, environmental insults, and lifestyle can interfere with fetus-placental development, leading to future diseases. The brain is a primary target for programming influence during neurodevelopment, and prenatal exposure to environmental stressors can result in long-term changes in brain structure and functionality, increasing the risk of neurodevelopmental disorders and adult-onset neurodegenerative diseases. A toxicological approach focused on the direct effect of stressors on the fetus has been applied to connect prenatal stress with the pathological outcomes on the brain. However, proper embryo/fetal development depends on the intrauterine environment and the functioning of the placenta, which delivers oxygen and nutrients to the developing baby as well as signaling molecules. The gestational exposure to single and/or multiple environmental stressors can significantly derange the homeostasis between maternal, placental and fetal factors involved in development. Understanding the molecular and functional responses to environmental stressors in both fetus and placenta during neuron development is crucial to assessing the environmental impact on the onset and development of neuronal pathologies. This project aims to define the direct effect on placental physiology and secretome and the direct and placental-dependent effect of environmental stress on neurons, focusing on diethyl phthalate (DEP) and fine particulate matter (PM).
Purpose
The present proposal is aimed at defining the direct and placental-dependent effect of environmental stressors on neurons to find out the mechanisms impacting neuronal developmental reprogramming and life long-function.
Expected results
1) Characterization of the effect of direct exposure to environmentally significant concentrations of DEP or PM on placental physiology and secretome
2) Characterization of the direct and placental-mediated effects of DEP or PM on neuronal development and life-long functions.
3) Characterization of placental-derived extracellular determinants impacting neuronal development and functionality
Activity 1.1 Effects of direct DEP or PM exposure on placenta viability (completed)
Activity 1.2 Investigate the effects of DEP or PM exposure on placental nutrient transport (not completed)
Activity 1.3 Investigate the effects of exposure to DEP or PM on placental explant secretion (not completed)
Activity 2.1 Investigate the effects of DEP or PM exposure on placental development (completed)
Activity 3.1 Effects of environmental stressors on in vitro neuronal differentiation (completed)
Activity 4.1 Analysis of the combined effects of placental secretome and direct stressors on neuronal differentiation (not completed)
Activity 4.2 Analysis of functional effects on hormonal receptors signaling (not completed)
Activity 4.3 Analysis of effects on mitochondrial structure (not completed)
Activity 4.4 Impact on mitochondrial bioenergetics, ROS generation and apoptotic cell death (not completed)
Activity 5.1 Analysis of the effects of soluble and vesicle placental secretome (not completed)
Activity 5.2 Analysis of placental secretome signature on neuronal cells (not completed)
State of the art
Fetal growth is regulated by a complex interaction of maternal, placental and fetal factors and any aberration of the in-utero environment might negatively affect developmental trajectories by altering gene expression, cell signal transduction and stress response. The brain is a primary target for such influences and prenatal exposure to environmental stressors (e.g. environmental and occupation pollutants, lifestyle and/or deficiency/oversupply of nutrients), during the sensitive period of neurodevelopment, may result in unwanted long-term changes in the brain structure and neuronal functionality. Epidemiological and experimental research has linked gestational exposure to environmental contaminants with aberration in neuron development and function that lead to an increased risk of neurodevelopmental disorders (NDDs) including disabilities in learning, memory and emotion. Besides, based on the “developmental origins of health and disease” (DOHaD) paradigm, the importance of in-utero exposure to stress conditions in determining a higher risk of developing the neurodegenerative disease (NDs) including Parkinson’s (PD) and Alzheimer’s disease (AD) later in life, has been suggested. A toxicological approach focused on the direct effect of neurotoxicant stressors (e.g., heavy metal, air pollution, pesticides) and/or endocrine-disrupting chemicals (EDCs) on the fetus has been commonly applied to connect the prenatal stress with the aberrant and pathological outcomes on brain. However, the proper embryo/fetal development is strictly dependent on the intrauterine environment and, consequently, on the proper growth and functioning of the placenta, the fetal organ interposed between the mother and the fetus. In addition to delivering essential oxygen and nutrients from the mother to the developing baby, the placenta plays an active role in the synthesis and release of signaling molecules into maternal and fetal circulation including steroids, cytokines, pregnancy-associated glycoproteins and microvesicles that serve to regulate maternal physiology for adaptation to pregnancy and fetal organ development. In particular, the placenta secretes extracellular vesicles (EVs), including exosomes, which reflect the pathophysiological state of the originating cells and can influence inflammation, apoptosis, and angiogenesis in the fetus. Recent studies show that gestational exposure to environmental chemicals alters placental metabolism and exosome release, modifying their protein, lipid, and microRNA content. For example, Bisphenol A (BPA) alters the secretion of the Macrophage Migration Inhibitory Factor (MIF), modifies placental levels of serotonin and dopamine, increases the production of oxidative stress markers, alters the expression of neurotrophic factors (BDNF) and pro-inflammatory cytokines (IL-1β, IL-6), and induces changes in microRNA levels with negative effects on neurodevelopment. Prenatal exposure to phthalates and airborne particulate matter also alters the placental transcriptome and the microRNA profile contained in placental-derived exosomes.
Overall, evidence indicates that the placenta responds by itself to maternal perturbation by altering its structure/function and changing blood flow, fetal nutrient supply and also the secretion of hormones and other signaling molecules. Thus, multiple mechanisms of cellular stress response activated by placental and fetal units may integrate and influence each other during in-utero environmental changes contributing to the perturbation of fetal programming.
Riferimento: PRIN 2022 PNRR – Codice progetto: P2022AXH5H – CUP: F53D23011290001
Investimento totale del progetto: 236.961,00
Partner : Università degli Studi di Siena
Coordinatore dell’UdR Università degli Studi Roma Tre: Marco Fiocchetti
