PROJECT SUMMARY
The goal of this K99/R00 project is to provide training to independence and enable the PI to test the hypothesis
that maternal-fetal exposures to environmental contaminants during early stages of fetal brain development
render the mature nervous system more susceptible to Alzheimer’s Disease and related dementia (ADRD).
Pregnant women are exposed to a large number of environmental contaminants in their daily life. Though the
placental-fetal barrier protects the fetus from most harm, some chemicals cross the barrier and can negatively
impact fetal development. The ‘Developmental Origins of Health and Disease’ hypothesis states that
developmental exposures are a trigger for life-long persistent effects, increasing the risk and susceptibility to
later-life age-related neurodegenerative diseases such as ADRD. These early-life exposures could permanently
change the homeostatic state of the nervous system in a way that seemingly retains normal structural
development but persistently alters function and disease-risk. We propose to develop an in vitro placental barrier
linked to human induced pluripotent stem cells (hiPSCs) developing into forebrain neurons. The PI will assess
whether exposures found in cord blood can cross this in vitro barrier using mass spectrometry. Then, we will
study whether selected compounds (heavy metal, pesticide, plasticizer) induce a persistently altered homeostatic
state in developing neurons at early age using imaging techniques as well as assessment of functional outcomes
(through micro-electrode array recordings) and genetic and metabolic outcomes (using single-cell RNA
sequencing). Finally, the PI will combine both models and develop an integrated placental-barrier – forebrain
model and expose to selected compounds. Exposed cultures will be matured and persistency will be assessed
again. Findings will be compared between different culture ages and different classes of compounds to develop
persistency signatures and get better understanding on how different classes of compounds induce this
neurological health risk state. Completing this study will advance the PI’s training in important new directions
that are enabled by the expertise of their mentors and collaborators and will help the PI reach their goal of
becoming an independent scientist. The team of mentors and collaborators is composed of experts in the
following fields of: placental biology and barrier modelling, exposomics, physiology of healthy brain aging,
bioinformatics and statistics, and neuro(epi)genetics. In collaboration with mentors, the PI will develop critical
skills that are required for a successful transition into a position as independent academic researcher in neuro-
and reproductive toxicology. This training will be accomplished through a focused development plan consisting
of didactic courses, close collaboration with mentors and collaborators. At the conclusion of this proposal, the PI
will have developed a human stem cell derived forebrain model to study persistent neurotoxic effects of trans-
placental developmental exposures to environmental pollutants.
