221 - Cord Blood Adductomics Define Placental-Lung Endotypes of BPD.

Publication Number: 221.4231

Elizabeth Brees, University of California, San Diego School of Medicine, La Jolla, CA, United States; Erika Lin, University of California, San Diego School of Medicine, San Diego, CA, United States; Janu Newar, University of California, San Diego School of Medicine, San Diego, CA, United States; Mana Parast, University of California, San Diego School of Medicine, La Jolla, CA, United States; William Funk, Northwestern University The Feinberg School of Medicine, Chicago, IL, United States; Karen Mestan, UC San Diego/Rady Children's Hospital, La Jolla, CA, United States

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of extremely preterm (EPT; ≤28 weeks gestation) birth, and is characterized by alveolar simplification and impaired development of the pulmonary vasculature. Several risk factors are associated with BPD including prenatal and postnatal exposures to oxidative stress. Oxygen free radicals form addition products (adducts) with proteins such as human serum albumin (HSA), which can be measured in plasma to evaluate exposure to oxidative stress. We have previously identified adducts of oxidative stress that are associated with BPD (Lin, et al. 2024). But the role of placental dysfunction in modifying these associations is not known. This is important to better understand the mechanisms that define distinct placental-lung endotypes of BPD.

Objective: To identify cord blood (CB) adducts that vary by BPD and placental dysfunction.

Design/Methods: 159 EPT and 49 full-term infants from the Northwestern Prentice Birth Cohort were studied. EPT infants with BPD (n=79) were further stratified by placental pathology into inflammatory (presence of acute and/or chronic inflammation; n=18), vascular (presence of maternal and/or fetal vascular malperfusion; n=16), or mixed (presence of both inflammatory and vascular histologic lesions; n=41). EPT healthy placentas (no pathology) with no BPD (n=6) served as controls. HSA was isolated from CB plasma via trypsin digestion, and analyzed using high-performance liquid chromatography-mass spectrometry to identify and quantify adducts. Data were analyzed using two-tailed t-tests with significance of P< 0.05.

Results: We identified 56 annotated (known) adducts. There was significant variability amongst infants stratified by BPD status and placental inflammation versus vascular dysfunction. As compared with controls:

1) The inflammatory-BPD group had increased concentrations of K adduct of T3 (unmodified T3 pathway), and decreased S-Methylethyl-sulfonylation (unclassified) and -Lys from C-terminus (truncation pathway).

2) The vascular-BPD group had increased Putative S-addition of acrolein (reactive aldehyde pathway).

3) The mixed placenta with BPD group had decreased -Lys from C-terminus and Cys34→Dehydroalanine (truncation pathway), and decreased S-Cys (possibly NH2→OH, -H2O) and S-Methylthiolation (small thiol pathway).

Conclusion(s): Cord blood adducts of oxidative stress vary with BPD, and are further modified by placental inflammation and vascular dysfunction. This approach to studying the neonatal-perinatal exposome can reveal novel endotypes of BPD defined by mechanisms of placenta-lung crosstalk.

Figure 1. EPT inflammatory placenta with BPD vs. EPT healthy placenta without BPD
Volcano plot comparing adduct log2 fold change vs. log10 p value in the inflammatory-BPD group vs. EPT healthy placenta without BPD (control) group. Significant adducts (P <0.05 on two-tailed t-test) are annotated on the graph.

Figure 2. EPT vascular placenta with BPD vs. EPT healthy placenta without BPD
Volcano plot comparing adduct log2 fold change vs. log10 p value in the vascular-BPD group vs. EPT healthy placenta without BPD (control) group. Significant adducts (P <0.05 on two-tailed t-test) are annotated on the graph.

Figure 3. EPT mixed placenta with BPD vs. EPT healthy placenta without BPD
Volcano plot comparing adduct log2 fold change vs. log10 p value in the mixed placenta with BPD group vs. EPT healthy placenta without BPD (control) group. Significant adducts (P <0.05 on two-tailed t-test) are annotated on the graph.