Metabolic Status and Expression Level of SREBP mRNA and Mir-33 Among Children Conceived by Assisted Reproductive...

Due to the growth in the global consumption of assisted reproductive technology (ART), it is possible that long-term health impacts on offspring have come into focus. ART has offered a welcome solution to infertility, but the fear has been on its effect on the metabolic health of children born on their behalf. Past studies indicate that ART-conceived individuals can have characteristic metabolic profiles relative to their naturally conceived (NC) peers and are therefore potentially predisposed to changes in lipid and glucose handling. Physiopathological glycolipid metabolism, a hallmark of cardiometabolic health, is believed to be modulated not only by environmental and other external factors but also by intracellular regulation proteins, including sterol regulatory element-binding protein (SREBP) and miR-33, although there is little evidence on the effects of ART on these regulatory pathways in early childhood.

This paper sought to compare the glycolipid metabolic profile of the kids who are in preschool age and who were conceived through ART and kids who were NC. The second aim was to study the expression of SREBP-1/2 and miR-33 in peripheral blood and the possible nature of the role of these players in regulating early-life metabolism.

A total of 220 children aged between 3 and 6 years were recruited of which complete data has been obtained from 206 children out of 98 that were conceived via in vitro fertilization/intracytoplasmic sperm injection (ICSI) (ART group) and 108 that were conceived naturally (NC group). Anthropometric measures-such as body weight, height, and waist circumference-to determine physical growth and obesity status were taken. Biochemical variables, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), fasting serum insulin (FINS), and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. A centrifugal column was used to obtain peripheral blood RNA, and relative gene expression levels of SREBP-1, SREBP-2, miR-33a, and miR-33b were measured by qPCR.

Compared with the IVF group, children in the ICSI group had significantly lower weight, height, and waist circumference (p < 0.05). In contrast, children in the NC group had significantly lower weight, BMI, and waist circumference, with all differences being statistically significant (p < 0.05). Additionally, compared with the IVF group, the NC group showed significantly increased levels of HDL-C and ApoA1 (p < 0.05). Meanwhile, the ICSI group had significantly higher ApoB levels and HOMA-IR scores (p < 0.05). Compared with the NC group, children in the ICSI group showed significantly higher levels of TG, ApoB, FINS, and HOMA-IR (p < 0.05), while ApoA1 levels were significantly lower (p < 0.05). When comparing clinical outcomes related to blood pressure, blood glucose, and blood lipids for abnormalities, there was no difference in incidence between the ART group and the NC group (p > 0.05). In addition, the expression of peripheral blood SREBP-1 mRNA, SREBP-2 mRNA, miR-33a, and miR-33b was compared. Compared with the IVF group, SREBP-1 mRNA and miR-33b levels in the NC group were significantly reduced, while miR-33a levels in the ICSI group were significantly decreased (p < 0.05). Compared with the NC group, SREBP-1 mRNA and SREBP-2 mRNA were significantly increased in the ICSI group (p < 0.05), while miR-33a was significantly decreased (p < 0.05). Correlation analysis showed that in the ART group, SREBP-1 mRNA expression levels were positively correlated with BMI, ApoB, fasting blood glucose, FINS, and HOMA-IR and negatively correlated with ApoA1. SREBP-2 mRNA levels were positively correlated with HOMA-IR and negatively correlated with ApoA1. Additionally, the expression levels of miR-33a were negatively correlated with HDL-C, while miR-33b levels were negatively correlated with both HDL-C and FINS.

Our data suggest that although children born by means of ART are otherwise normal in their glycolipid metabolism, they are more prone to overweight and obesity and have different biochemical and molecular characteristics than NC children. The upregulation of miR-33b, SREBP-1, and SREBP-2 observed indicates that ART can play a role in regulating the process of glycolipid metabolism during early childhood at a molecular level. Such alterations might not present the form of a blatant metabolic condition at this age but may consist of initial symptoms of future troublesome metabolic health. Prolonged follow-up of the ART offspring and additional mechanistic work are desirable to be able to determine whether these early changes are the underlying reasons behind higher metabolic risk as adults.