P-224 Basonuclin 1 prevents intrauterine growth restriction via inhibiting necroptosis

Abstract

Abstract Study question Is basonuclin 1 (BNC1) involved in intrauterine growth restriction (IUGR), and what’s the underlying mechanism? Summary answer BNC1 is significantly decreased in the placenta of IUGR patients. BNC1 deficiency engenders IUGR in Bnc1 truncation mutation (Bnc1tr/tr) mice model by inducing placental necroptosis. What is known already IUGR is among the leading causes of perinatal morbidity and mortality. IUGR occurs due to multiple factors, including genetic, placental, fetal, and maternal factors. Among which genetic factors remain largely unknown. Our previous exploration found that Bnc1 mutationmice exhibit low birth weight and survival rates, indicating BNC1 may play a potential role in fetal and placental development. Necroptosis is a recently recognized cell death pathway that may contribute to placental pathophysiology in IUGR patients. While the underlying mechanism remains largely unknown. Study design, size, duration A clinical retrospective cohort study of 40 IUGR patients (diagnosed by Hadlock ultrasound measurements) and 40 controls were included (2017–2022) for placenta collection. Bnc1 targeted mutation mouse was on a C57BL/6 J background. Male and female mice of the Bnc1+/tr genotype were mated to produce Bnc1+/+, Bnc1+/tr, and Bnc1tr/tr mice. Placenta and fetuses were obtained on the 15th and 18th days of pregnancy. Participants/materials, setting, methods The following analyses were performed: (i) Immunohistochemistry for detecting the location and expression of BNC1 in the placenta of humans and mice, (ii) placental and fetal weights for evaluation of IUGR development, (iii) morphometric evaluation of fetal utilizing Alcian blue and alizarin red staining, (iv) morphometric evaluation of placental compartments utilizing H&E staining, TUNEL staining, and TEM analysis, (v) RNA sequencing (RNA-seq) of placental tissues. Main results and the role of chance BNC1 was specifically highly expressed in trophoblasts and endothelial cells in the early and mature placental development stages of humans and mice. The expression of BNC1 was significantly decreased in the placenta of IUGR patients compared to the control group (P < 0.0001). In the mice model, the number of Bnc1tr/tr fetuses was significantly decreased compared with wild-type Bnc1+/+ fetuses on the 18th day of pregnancy. While the number of Bnc1tr/tr fetuses and Bnc1+/+ fetuses was similar on the 15th day of pregnancy, indicating the loss of Bnc1tr/tr fetuses between the two stages. Besides, both the Bnc1tr/tr fetal and placental weights were significantly decreased on the 15th day of pregnancy compared with Bnc1+/+ fetuses and placenta (P < 0.01). The Bnc1 truncation mutation caused poor development of the placental labyrinthine layer with an increased number of TUNEL-positive foci. Transmission electron microscopy also revealed a disorganized labyrinthine layer with defects in cytoplasm translucence, loss of plasma membrane integrity, swollen mitochondria, and decondensed chromatin. Finally, RNA sequencing of placental tissues indicated BNC1 deficiency-induced IUGR may be modulated by necroptosis. In conclusion, we found a relationship between the disturbed BNC1 expression and the occurrence of IUGR through necroptosis. Limitations, reasons for caution This study used only Bnc1 truncation mutation mice model, the other animal model with placenta-conditional knockout mice was needed to consolidate the results. Besides, further mechanism exploration should be conducted in both human and mouse cell lines. Wider implications of the findings Our work suggests a new gene related to the development of IUGR, which provides early diagnosis and treatment for managing IUGR, thus improving outcomes for both fetal and gravida. Trial registration number not applicable