Biochemical Hazards during Three Phases of Assisted Reproductive Technology: Repercussions Associated with Epigenesis and Imprinting

Abstract

Medically assisted reproduction, now considered a routine, successful treatment for infertility worldwide, has produced at least 8 million live births. However, a growing body of evidence is pointing toward an increased incidence of epigenetic/imprinting disorders in the offspring, raising concern that the techniques involved may have an impact on crucial stages of early embryo and fetal development highly vulnerable to epigenetic influence. In this paper, the key role of methylation processes in epigenesis, namely the essential biochemical/metabolic pathways involving folates and one-carbon cycles necessary for correct DNA/histone methylation, is discussed. Furthermore, potential contributors to epigenetics dysregulation during the three phases of assisted reproduction: preparation for and controlled ovarian hyperstimulation (COH); methylation processes during the preimplantation embryo culture stages; the effects of unmetabolized folic acid (UMFA) during embryogenesis on imprinting methyl “tags”, are described. Advances in technology have opened a window into developmental processes that were previously inaccessible to research: it is now clear that ART procedures have the potential to influence DNA methylation in embryonic and fetal life, with an impact on health and disease risk in future generations. Critical re-evaluation of protocols and procedures is now an urgent priority, with a focus on interventions targeted toward improving ART procedures, with special attention to in vitro culture protocols and the effects of excessive folic acid intake.

Does supplementation of oocytes with additional mtDNA influence developmental outcome?

“…We know from our previous work that although a number of differentially methylated regions were observed at the blastocyst stage following mtDNA supplementation, imprinted regions were not affected. 20 However, imprinting anomalies have been associated with some assisted reproductive technologies 53 , 54 , 55 and incomplete reprogramming of the somatic cell following nuclear transfer. 56 In samples isolated from tail, we did not observe any potential imprinting defects from the regions we analyzed which demonstrates consistency with the setting of early imprinting programming in the mtDNA supplemented embryo.…”

Folic acid supplementation and its effects on the oestrus cycle of rats.

“…Empirical data indicates that increased concentrations of folic acid can interfere with the typical functioning of reproductive hormones, potentially impacting fertility, menstrual cycles, and hormone-related processes. 9,19 These findings raise concerns about the potential implications for both male and female reproductive systems.…”

“…Folic acid functions as a chemical that disrupts the endocrine system. 9 These chemicals act on androgen receptors, interfering with their normal signaling and actions. 10 Disrupting the androgen receptor signaling pathway affects the hypothalamic-pituitary-gonadal axis, leading to increased secretion of sex hormones such as GnRH, LH, and FSH.…”

The role of maternal choline, folate and one‐carbon metabolism in mediating the impact of prenatal alcohol exposure on placental and fetal development

“…Taken together, altered absorption and/or demand for folate and choline as a result of alcohol consumption probably exacerbates the inadequate dietary intake and increased requirements for these factors during pregnancy. This may be particularly important during early pregnancy because the developing blastocyst is highly sensitive to changes in micronutrient availability (Dos Santos Mendonça‐Soares et al., 2022 ; Estrada‐Cortés et al., 2020 ; Menezo et al., 2022 ).…”