# Germline-mediated Transgenerational Epigenetic Inheritance of Paternal Epimutations Induced by a High Fat Diet

> **NIH NIH P50** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2022 · $292,737

## Abstract

Project 3 – “Germline-mediated intergenerational epigenetic inheritance of paternal
epimutations induced by a high fat diet”
Project Abstract/Summary: Abundant data from many labs has established that environmental exposures
can predispose development of disease characteristics in an exposed male and also in that male’s offspring, even
if the offspring are never, themselves, directly exposed to the original disruptive influence. In addition to
chemical exposures, deleterious lifestyle choices such as consumption of an unhealthy diet, lack of exercise,
smoking, etc., can predispose disruptions of the epigenome (epimutations) that can be subsequently propagated
to many cells or organs in the exposed male’s body, including to his sperm. Once in the exposed male’s sperm,
lifestyle-induced epimutations can then be transmitted to the male’s offspring on the basis of epigenetic
inheritance, where they can predispose development of similar disease characteristics. Though this phenomenon
has now been studied for >10 years, there remains very little information about the underlying molecular
mechanisms. We propose a novel, comprehensive, mechanism-focused set of experiments to be conducted using
a mouse model subjected to two effects mimicking deleterious lifestyle choices in humans – i) consumption of a
high-fat diet and ii) lack of a structured exercise regime. Specifically, we propose experiments designed to 1)
identify the specific combination of epigenetic parameters involved in transmission of lifestyle-induced
epimutations from sperm to the ensuing fetus, 2) reveal the extent to, and mechanisms by, which resulting
epimutations in the F1 fetus are propagated to developing somatic and germ cell lineages and on into the
immature and adult offspring, 3) determine the extent of intercellular homo- versus hetero-geneity of lifestyle-
induced epimutations in spermatogenic cells of the sire and in relevant germ and somatic cell types in his
offspring, 4) discern the mechanisms by which inherited epimutations contribute to dysregulated gene
expression in tissues relevant to aberrant/disease phenotypes in the offspring, 5) elucidate dysregulated
pathways responsible for defective or disease states among offspring of sires transmitting lifestyle-induced
epimutations, and 6) determine the extent to which the incidence of all of these deleterious effects can be
reduced by transition of males from an unhealthy to a healthy life style, including a normal diet and exercise.
A broad range of analyses of epigenomic parameters is proposed as a means to investigate mechanisms
underlying the etiology and paternal transmission of lifestyle-induced, intergenerational epimutations. Results
of the proposed research will inform future efforts to prevent, diagnose, treat or reverse the deleterious
epimutagenic effects of siring offspring while engaged in an unhealthy life style.

## Key facts

- **NIH application ID:** 10260436
- **Project number:** 5P50HD098593-03
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** John R MCCARREY
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $292,737
- **Award type:** 5
- **Project period:** 2019-09-13 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260436

## Citation

> US National Institutes of Health, RePORTER application 10260436, Germline-mediated Transgenerational Epigenetic Inheritance of Paternal Epimutations Induced by a High Fat Diet (5P50HD098593-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10260436. Licensed CC0.

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