Germline transmission of epigenetic alterations to offspring

ABSTRACT: The overall goal of this research program is to delineate the role of germline
epigenetic alterations (epimutations) in the onset and progression of inter-and transgenerational
reproductive defects. So far, published scientific literature suggests that environmentally induced
epigenetic alterations, mainly DNA methylation, histone modifications, and RNA modifications
(epitranscriptome), are transmitted to subsequent generations via germline (eggs or sperm)1.
However, the role of observed epimutations in the development of reproductive phenotypes is not
well understood because of a lack of clear understanding of PGC to germline and germline-to
soma transfer of reprogramming-resistant epimutations during the turnover of generations. Here
in the proposed study, we are asking three big questions: a) Do germline epimutations establish
age and developmental stage specifically in males? b) Do ancestrally established
transgenerational epimutations predispose future generations to increased risks for reproductive
impairment if exposed again to emerging environmental chemicals of concern? c) Is the role of
the observed epimutations in the development of progression of phenotypic traits causative or
correlative? This R01 research project will systematically answer these questions in three different
aims. BPA will be used as a ubiquitous model endocrine-disrupting chemical (EDC), and
Bisphenol S (BPS) will be used as an emerging contaminant of concern, and medaka fish as a
comparative vertebrate animal model. Aim 1 will test the hypothesis that male germ cells at all
stages of development are susceptible to BPA, the model EDC. Aim 2 will test the hypothesis that
exposure of the F3 generation offspring with pre-existing epimutations to emerging contaminants
will result in an increased incidence of reproductive impairment. Aim 3 will test the hypothesis
that the EDC-induced epimutations are associated with reduced fertility in males and females and
that these epimutations can be corrected by reprogrammable CRISPR-dCas9 epigenome editing
in vivo. The project will identify footprints of the past exposure, determine the role of
epimutations in reproductive impairment, determine whether inherited epimutations predispose
current and future generations to increased risks of reproductive health due to exposure to
emerging contaminants of concern, and provide significant insights into mechanisms underlying
germline transmission of the epigenome and longitudinal health risks of exposure. Understanding
of key time points during which epimutations transfer would provide insights into strategies for
the mitigation of future estrogenic chemical-induced reproductive health effects in humans.

Grant Number: 5R01ES032452-06
NIH Institute/Center: NIH
Principal Investigator: Ramji Bhandari