# Role of SRY in transgenerational transmission of alcohol epigenetic marks on proopiomelanocortin gene

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $348,750

## Abstract

Project Summary/Abstract
Children and young adults who were exposed to alcohol during fetal life often show fetal alcohol spectrum
disorders (FASD) consisting of learning disabilities, emotional disturbances, stress abnormalities and immune
incompetence. Furthermore, some grandparents who had alcohol-related medical problems often had
grandchildren with a higher rate of fetal alcohol syndrome than those grandparents without alcohol-related
medical problems. Epidemiological studies also have shown association of paternal alcohol consumption with
deficiencies in offspring—effects which are typically found with maternal alcohol exposure. However, the
process underlying the heritability of alcohol-induced health issues is not clearly understood. Our recent
studies identified an epigenetic mechanism in the heritable effect of fetal alcohol on stress response
abnormalities and immune dysfunctions. These studies showed that the proopiomelanocortin (Pomc) gene,
which negatively controls the functions of the stress axis and stimulates the functions of the immune systems,
is hypermethylated while the response of stress axis hormones and the production of the cytokine interferon-γ
(IFN-γ) is dysregulated in fetal alcohol exposed offspring for three generations via the male germline. However,
the process by which these epigenetic variants induced by fetal alcohol are transmitted from parents to
offspring through multiple generations has not been established. We hypothesize that a transcription factor like
sex-determining region Y (SRY), which has significant control over Pomc gene expression, undergoes
heritable epigenetic modifications by fetal alcohol exposures that in turn modify the expression of the Pomc
gene and its endophenotypes. The objective of this proposal is to determine the heritable epigenetic effects of
alcohol exposure during the prenatal period on SRY-mediated Pomc gene expression and its endophenotypes,
i.e., the stress hormone response and IFN-γ production to an immune challenge, in isogenic Fischer 344 rats.
This research aim will be achieved by determining the relationship between the fetal alcohol epigenetic marks
on Pomc and its endophenotypes with the epigenetic marks on the Sry gene in the isogenic rat population in
three generations of offspring, studying the interaction between SRY and Pomc at the molecular level, and
evaluating whether increased methylation affects SRY interaction with the Pomc promoter and contributes to
fetal alcohol effects on Pomc and its endophenotypes. Various state of the art techniques will be employed
involving promoter methylation, promoter demethylation, promoter activity, mutational analysis, gene knock
down, in vivo electroporation for gene overexpression, and stress and immune response studies. These
studies will establish the process by which developmental alcohol exposure induces gene expression variants
in the offspring and how they are transmitted to next generations. Knowledge on the process in...

## Key facts

- **NIH application ID:** 9961332
- **Project number:** 5R01AA025359-04
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** DIPAK KUMAR SARKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,750
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961332

## Citation

> US National Institutes of Health, RePORTER application 9961332, Role of SRY in transgenerational transmission of alcohol epigenetic marks on proopiomelanocortin gene (5R01AA025359-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961332. Licensed CC0.

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