Chromosome 21 and Beyond: Oxidative Stress as Novel Biomarker in Down Syndrome, suggests study

Oxidative stress, linked to Down syndrome (DS), is exacerbated by the presence of numerous genes related to redox homeostasis on chromosome 21. Recent investigation evaluated transcription factors NRF2 and NFKB, alongside antioxidant enzymes CSE and NQO1, in amniotic fluid (AF) and maternal serum (MS) as biomarkers for non-invasive prenatal screening for DS.

Study Design and Methodology

The study utilized a case-control design, enrolling 65 pregnant women undergoing amniocentesis. Participants were categorized into two groups: those with confirmed DS (28 cases) and those with normal karyotypes (37 controls). The analysis focused on biomarker levels in both AF and MS, employing enzyme-linked immunosorbent assays to quantify NQO1, NRF2, CSE, and NFKB concentrations.

Key Results and Comparisons

Results indicate that NQO1 levels were substantially elevated in both AF (mean 924.84 ng/ml vs. 505.62 ng/ml) and MS (716.216 ng/ml vs. 394.87 ng/ml) in the DS group compared to controls. Conversely, NRF2 levels were significantly reduced in both fluids for DS cases. MS CSE levels were higher in DS instances but not in AF. No substantial variations were observed in NFKB levels. Diagnostic performance assessments revealed that NQO1-AS and NQO1-MS exhibited significant predictive capabilities for DS, with optimal cut-off values of 800 ng/ml (85% sensitivity, 75% specificity) and 650 ng/ml (80% sensitivity, 70% specificity), respectively. Conversely, NRF2 demonstrated poor diagnostic performance, suggesting limited utility in primary screening protocols.

Relationship between Biomarkers and Oxidative Stress

The study highlighted a complex relationship between biomarkers, showing increased NQO1 and CSE alongside decreased NRF2 levels in DS pregnancies, challenging existing notions of NRF2’s regulatory role during oxidative stress. It is hypothesized that chronic oxidative conditions may result in NRF2 pathway downregulation, promoting a compensatory response via increased antioxidant synthesis, which aligns with findings of altered oxidative stress pathways in other chronic conditions.

Implications for Future Research

This research underscores the importance of NQO1 as a potential biomarker for non-invasive prenatal screening of DS and suggests further investigation into the regulatory mechanisms underlying redox balance disruptions in affected pregnancies. Larger, multicenter studies are recommended to validate these findings and explore the combined use of multiple biomarkers to enhance screening accuracy while minimizing invasive interventions.

Key Points -

- -Oxidative Stress and Genetic Links-: The investigation reveals a strong connection between oxidative stress and Down syndrome (DS), emphasizing the role of several redox homeostasis-related genes located on chromosome 21, which may exacerbate oxidative stress conditions.

- -Study Design and Participant Grouping-: A case-control approach was adopted, involving 65 pregnant women undergoing amniocentesis, with 28 women diagnosed with DS and 37 controls with normal karyotypes, to assess potential biomarker viability for prenatal screening.

- -Biomarker Concentrations-: Significant elevations in NQO1 levels were identified in both amniotic fluid (AF) and maternal serum (MS) in the DS cohort when compared to controls, alongside reduced NRF2 levels in both biological samples, indicating distinct biomarker patterns associated with DS.

- -Diagnostic Performance of Biomarkers-: NQO1 levels showed predictive capabilities for diagnosing DS, establishing cut-off values of 800 ng/ml in AF and 650 ng/ml in MS, yielding satisfactory sensitivity and specificity metrics, while NRF2 showed insufficient diagnostic performance, questioning its applicability in screening.

- -Complex Interplay of Oxidative Stress Markers-: The study presents a nuanced interaction between biomarkers, with increased NQO1 and CSE linked to decreased NRF2 levels in DS, implying potential downregulation of the NRF2 pathway due to sustained oxidative stress conditions, suggesting a compensatory increase in antioxidant production.

- -Future Research Directions-: Highlighting NQO1’s potential as a biomarker for non-invasive DS screening, the study advocates for additional research into the mechanisms of redox imbalance in affected pregnancies, along with larger multicenter trials to validate and enhance biomarker combinations for more accurate screening strategies.

Reference –

Sinem Tekin et al. (2025). Oxidative Stress Biomarkers As Novel Screening Tools For Trisomy 21: A Case-Control Study. *BMC Pregnancy And Childbirth*, 25. https://doi.org/10.1186/s12884-025-07601-4.