Prenatal Environmental Stressors and DNA Methylation Levels in Placenta and Peripheral Tissues of Mothers and Neonates Evaluated by Applying Artificial Neural Networks

Abstract

Exposure to environmental stressors during pregnancy plays an important role in influencing subsequent susceptibility to certain chronic diseases through the modulation of epigenetic mechanisms, including DNA methylation. Our aim was to explore the connections between environmental exposures during gestation with DNA methylation of placental cells, maternal and neonatal buccal cells by applying artificial neural networks (ANNs). A total of 28 mother–infant pairs were enrolled. Data on gestational exposure to adverse environmental factors and on mother health status were collected through the administration of a questionnaire. DNA methylation analyses at both gene-specific and global level were analyzed in placentas, maternal and neonatal buccal cells. In the placenta, the concentrations of various metals and dioxins were also analyzed. Analysis of ANNs revealed that suboptimal birth weight is associated with placental H19 methylation, maternal stress during pregnancy with methylation levels of NR3C1 and BDNF in placentas and mother’s buccal DNA, respectively, and exposure to air pollutants with maternal MGMT methylation. Associations were also observed between placental concentrations of lead, chromium, cadmium and mercury with methylation levels of OXTR in placentas, HSD11B2 in maternal buccal cells and placentas, MECP2 in neonatal buccal cells, and MTHFR in maternal buccal cells. Furthermore, dioxin concentrations were associated with placental RELN, neonatal HSD11B2 and maternal H19 gene methylation levels. Current results suggest that exposure of pregnant women to environmental stressors during pregnancy could induce aberrant methylation levels in genes linked to several pathways important for embryogenesis in both the placenta, potentially affecting foetal development, and in the peripheral tissues of mothers and infants, potentially providing peripheral biomarkers of environmental exposure.

Current perspectives on perinatal mental health and neurobehavioral development: focus on regulation, coregulation and self-regulation

“…We refer to [73 ▪▪ ,123] for recent overviews. We cite recent reviews addressing these complex, multifacted processes involving: mother-fetus-placenta unit [78]; HPA axis and cortisol [120,124 ▪ ,125]; autonomic nervous system [125]; iron deficiency [126]; maternal inflammation and offspring microglial activity [127]; mitochondria [128]; microbiome [10,129–131]; maternal metabolic risk factors including diabetes, obesity, undernutrition, specific macro- and micronutrient intake (e.g., long-chain polyunsaturated fatty acids (PUFAs) [132–135]; epigenetic changes, epigenome wide associations studies, relevant for e.g., the HPA axis or oxytocin system [136] including DNA methylation, histone modification, microRNA and other-non coding RNA [73 ▪▪ ,135,137–139] or multiomics data (transcriptomics, proteomics, metabolomics, and microbiomics [140]); telomere length [57]; paternal mediated effects [141,142]; oxidative stress [143], breast milk composition [78]; oxytocin system [73 ▪▪ ]; serotonin functions (e.g., SCL6A4) [73 ▪▪ ]; brain-derived neurotrophic factor (BDNF) [73 ▪▪ ]; structural and functional brain alterations beyond regions previously identified as relevant (i.e., prefrontal cortex, hippocampus, amygdala (limbic system)) additionally including basal ganglia, anterior cingulate cortex, thalamus, middle and superior frontal gyri, occipital gyrus and precentral gyrus [9,31,108].…”

Effect of night shift work on metabolic syndrome in adults who suffered from earthquake stress in early life

“…Additionally, deficiencies of micronutrients in pregnant mother rats, such as calcium, zinc and vitamin D, are linked to offspring MetS ( 22 ). Furthermore， prenatal stress may lead to abnormal methylation levels of genes associated with important pathways of embryogenesis in the placenta, possibly affecting fetal development, as well as the peripheral tissues of the mother and baby ( 23 ). Both animal and human studies have confirmed that epigenetic mechanisms are important modulators of the susceptibility of offspring exposed to stressors during pregnancy to chronic diseases, especially metabolic diseases ( 24 , 25 ).…”

(Epi)genetic Aspects of Metabolic Syndrome Pathogenesis in Relation to Brain-derived Neurotrophic Factor Expression: A Review

“…84 Methylation of the BDNF gene also has been detected in the placenta, umbilical cord, and venous blood of women who had suffered traumatic events during pregnancy and in buccal mucosa samples from newborns at 2 months of age (exposed to intrauterine stress). 85 Methyl-CpG-binding protein 2 (MeCP2) interacts with methylated DNA in the brain and inhibits/activates gene transcription. Mutations of MeCP2 and knockout in hypothalamic neurons (e.g., POMC ARC and Sim1) lead to hyperphagia and obesity.…”

“…86 The MECP2 gene is involved in the development of MetS, and the MECP2 protein controls body weight through post-translational modifications. 85 It has been found that mice with a MeCP2 muta-tion/deletion have lower levels of BDNF in the brain. At the same time, BDNF is involved in the phosphorylation of MeCP2 (antidepressant effect).…”