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Imprinted Gene Regulation by in utero Lead Exposure in Mice

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY The objective of this study is to determine epigenetic mechanisms that impact genomic imprinting upon in utero exposure of mice to human-relevant levels of lead (Pb). Pb is an infamous environmental exposure to human populations in the US and around the world, due in part to its neurotoxic effects. Pb exposure during early development has been linked to adverse health outcomes later in life. Preliminary data generated for this grant indicates that in utero and perinatal Pb exposure increases placenta/embryo size, and alters the DNA methylation of imprinted genes, respectively. However, the molecular mechanisms by which Pb exposure reprograms genomic imprinting during early gestation remain largely unknown. Imprinted genes are epigenetically regulated in a parent-of-origin specific manner with their mono-allelic expression driving critical periods of development. Known mechanisms of genomic imprinting include the 1) long non-coding RNA (lncRNA) and 2) insulator models, each of which program allele-specific regulation of imprinting control regions. Although dysfunctional genomic imprinting is implicated in several human diseases, the mechanisms leading to toxicant-induced imprinting dysregulation by the two models remain poorly understood. Using an established Pb exposure mouse model, this study seeks to determine in utero mechanisms that impact genomic imprinting and health effects from altered epigenetic reprogramming. Thus, female animals exposed to Pb two weeks prior to mating through 13-14 days post-conception will be used in the following Aims: 1) Determine fetal sex-specific imprinting dysregulation associated with in utero Pb exposure in mouse placenta, 2) Assess allele- and sex-specific mechanisms of in utero Pb exposure regulating genomic imprinting in the brain. Pb-exposed animals will be compared against controls to investigate genomic imprinting mechanisms in the lncRNA and insulator models by characterizing sex-, tissue-, and developmental stage-specific imprinted gene dysregulation via phenotypic, gene expression, DNA methylation, and immunohistochemical analyses. This study will reveal Pb-associated lncRNA mechanisms that inform the current epigenetic reprogramming by fetal sex. The University of Michigan provides an ideal environment to conduct the proposed research in collaboration with multiple core facilities outlined herein. The candidate will receive mentorship from a multidisciplinary team of experts to: 1) Gain proficiency in computational and statistical skills required for data analysis; 2) Acquire expertise in developmental toxicological research and mechanistic investigation; and 3) Build skills critical for leadership, teaching and mentoring, laboratory management, and grantsmanship. The proposed study will address fundamental knowledge gaps of genomic imprinting in the field to inform potential Pb-induced disease interventions. The training and research goals established in this K01 proposal constitute an exceptional foundation to ensure the candidate success in obtaining research independence.

Up to $154K

2027-01-31

health research

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Imprinted Gene Regulation by in utero Lead Exposure in Mice

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Grants

Imprinted Gene Regulation by in utero Lead Exposure in Mice

Improve Access to National Park Service Archives

Improve Archeological Site and Survey Location Data in ASMIS

Improve control strategies for invasive plants and fungal pathogens in Hawaii Volcanoes National Park

Improve Landscape for Interpretation

Improve the Quality of Life of older cancer patients

Improve Trail Signage and Remove Graffiti at Joshua Tree National Park

Improve Treatment of Condors for Lead Exposures by Assessing Efficacy of Current Protocol

Improve Visitor Experience at Cane River NHP and Cane River National NHA

Improve Visitor Use Areas throughout Little Bighorn National Battlefield

Improved Aminopyridine Analogs for Symptomatic Treatment of Botulism

Improved Compliance with Labor Laws in the Country of Georgia

Improved post-stroke walking balance through adaptive multisensory augmentation

Improvement and expansion of MCGO

Improvements to Biological Research Collections

Improving advance care planning by persons living with dementia using narrative video games

Improving Bronchoalveolar Lavage To Enhance Diagnostic Yield Of Pulmonary Complications

Improving capabilities of law enforcement to counter climate-related challenges

Improving Chronic Conditions Through Inexpensive Interventions

Improving Chronic Conditions Through Inexpensive Interventions

Improving circularity of multilayer flexible plastic food contact packaging

Improving climate resilience of navigable inland waterways, their surroundings and related water infrastructure

Improving Cognitive Rehabilitation Outcomes for Veterans with mTBI+PTSD

Improving compliance with labor laws in Mexico