# Epigenetic mechanisms in Transgenerational Effects of an Environmental Pollutant

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2021 · $488,319

## Abstract

Abstract
Bacterial infections during neonatal phase cause high rates of morbidity and mortality, and in developing
countries are responsible for 26% of deaths. Environmental factors present during pregnancy are known to
impact life-threatening infections in newborns, including Staph. aureus infections, although the mechanisms are
unclear. Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant, which acts through the cytosolic
aryl hydrocarbon receptor (AhR). While AhR has been well characterized for its role in regulating toxicity
mediated by TCDD, recently, AhR activation was shown to regulate T cell differentiation into T regs or Th17
cells. We have generated exciting preliminary data indicating that AhR activation by TCDD suppresses T cell
response to Staphylococcal enterotoxin B (SEB) and that this is mediated by epigenetic pathways including
dysregulation in microRNA (miR) expression, DNA methylation, and histone modifications in activated T cells.
More importantly, our studies have suggested that TCDD may exert transgenerational epigenetic effects on T
cells. Based on the importance of Staph infections discussed above, we will use SEB as an antigen to
test the central hypothesis that AhR activation of Vβ8+ T cells by TCDD, plays a crucial role in reducing
pro-inflammatory Th1/Th17 cells as well as increasing anti-inflammatory Tregs and its subsets by
modulating miR expression, and that this may depend on DNA methylation, histone modifications and
chromatin remodeling that could be transmitted transgenerationally. Inasmuch as, SEB can activate Vβ8+
T cells which constitute ~30% of peripheral T cells, our studies are aimed at determining whether TCDD-induced
changes persist in F0, F1, F2, and F3 generations following maternal exposure during pregnancy to TCDD or
maternal/paternal exposure prior to mating (F0). In Aim 1, we will determine the transgenerational effects of
TCDD on SEB-induced CD4+ T cell differentiation. We will test the effect of TCDD on the TCR clonality and
diversity of the Vβ8+ CD4+ T cell response (Th1, 2, 17, Tregs) to SEB. In Aim 2, we will study the role of specific
miRs in CD4+ T cell differentiation in F0-F3 generations. Furthermore, transfection of T cells with specific miR
mimics or antagomirs will be performed to reverse T cell differentiation induced by TCDD and determine whether
the effects persist across generations. In Aim 3, we will determine the role of genome-wide and locus-specific
DNA methylation on CpG sites on promoters of specific miR that regulate differential expression of Th/Treg
response to SEB across the generations. Aim 4 will elucidate the permissive and repressive histone modification
and chromatin accessibility in TCDD-mediated transgenerational dysregulation of miR involved in CD4+ T cell
differentiation. Lastly, whether these changes are imprinted through male or female germline will be assessed.
The proposed studies are highly significant in that novel epigenetic pathways of TCDD-me...

## Key facts

- **NIH application ID:** 10169438
- **Project number:** 5R01ES030144-03
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Mitzi Nagarkatti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $488,319
- **Award type:** 5
- **Project period:** 2019-09-24 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169438

## Citation

> US National Institutes of Health, RePORTER application 10169438, Epigenetic mechanisms in Transgenerational Effects of an Environmental Pollutant (5R01ES030144-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169438. Licensed CC0.

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