NYMC Student Theses and Dissertations

Date of Award

5-28-2025

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Pathology

First Advisor

Brian B. Ratliff, PhD

Second Advisor

May M. Rabadi, PhD

Third Advisor

Michael S. Wolin, PhD

Abstract

Proper nutrition is crucial during pregnancy to support fetal and placental development. Failure to meet these nutritional needs can result in adverse health outcomes for both mother and baby. Despite its high prevalence in underdeveloped countries, maternal undernourishment is a public health issue worldwide. There are several possible causes of maternal undernourishment, and these can occur alone or in combination, such as poor access to nutrition, hyperemesis gravidarum, and drug use. This condition can adversely affect placental development and function to the extent of placental insufficiency, perturbing the entire pregnancy. The placenta is responsible not only for hormonally and physically maintaining the pregnancy but also for providing nutrients to the fetus while removing harmful waste products. Fetuin-B, a hepatokine identified as a possible biomarker in other gestational pathologies, was significantly upregulated in maternally undernourished placentas. It is hypothesized that this upregulation of fetuin-B in combination with oxidative stress during maternal undernourishment could play a significant role in placental insufficiency, ranging from the function of the whole organ down to the trophoblast (extraembryonic stem cells forming the placenta) level. Several pharmaceutical interventions were utilized to identify pathway contribution and as possible therapeutics: Tempol for oxidative stress, MitoTEMPO for mitochondrial superoxide production, and TAK-242 for TLR4 involvement.

A previously established mouse model was utilized to examine the consequences of maternal undernourishment on the placenta. Pregnant dams were fed a reduced protein chow at a caloric deficit. In the past, this model consistently produced low-birth-weight offspring, supporting its effectiveness. At the whole organ level, placental vascularization (immunofluorescent staining), vascular reactivity (wire myography), and blood flow (laser- Doppler flowmetry) were measured. Placental explants and primary trophoblast cultures xi were probed for oxidative stress, proliferation, cell death, and cell differentiation (immunofluorescent staining). A commercial trophoblast cell line, HTR-8/SVneo, was utilized to examine the isolated effects of fetuin-B on trophoblast cells regarding oxidative stress, proliferation, cell death, TLR4 activation, and NF-kB expression. There was particular interest in mitochondrial function and how it is affected by maternal undernourishment and fetuin-B. Both primary and commercial trophoblasts treated with fetuin-B were compared in terms of mitochondrial superoxide production, antioxidant levels, metabolism, and electron transport chain complex activity.

Studies showed that maternal undernourishment, while upregulating oxidative stress and fetuin-B, perturbed placental development, reduced trophoblast pools, and impaired vascular function. Fetuin-B upregulation was exposed as a detrimental factor promoting excess oxidative stress in a positive feedback loop. It could account for many of the changes in the placenta during maternal undernourishment. Treatment with fetuin-B activates TLR4, increases NF-kB p65 expression, increases oxidative stress, and disrupts mitochondrial function. As revealed by the application of pharmaceutical agents, cellular oxidative stress, mitochondrial oxidative stress, and TLR4 activation contribute to these fetuin-B-linked outcomes.

Maternal undernourishment, through the increase in oxidative stress and upregulation of fetuin-B, impairs placental development and proper vascular function, negatively impacts trophoblasts that form the placenta, and promotes mitochondrial dysfunction. This study identified possible therapeutic agents that could serve as add-on treatments to a proper diet. The findings are widely applicable to placental insufficiency and shed light on the mechanisms involved in this condition that are commonly associated with obstetric pathologies.

Keywords

placenta, trophoblast, maternal undernutrition, mitochondria, oxidative stress, fetuin-B

Disciplines

Animal Experimentation and Research | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Human and Clinical Nutrition | Medicine and Health Sciences

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