# Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance

> **NIH ES R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2026 · $633,756

## Abstract

Studies in animal models linked gestational exposures to endocrine disrupting chemicals (EDCs) with the
onset of disease in exposed and unexposed descendants. Many groups found such transgenerational effects
of chemical exposures, which were proposed to be examples of epigenetic inheritance. Transgenerational
effects of environmental exposures have substantial support in the literature. Yet the concept that responses to
environmental exposures can be transmitted to subsequent generations through the germline without DNA
mutations remains controversial because the underlying mechanisms have not been explained satisfactorily.
Understanding how effects of environmental exposures are transmitted to unexposed generations without DNA
mutations is a fundamental, unanswered question in biology. We developed a highly reproducible animal
model for transgenerational inheritance of obesity. When pregnant F0 mouse dams were treated with
environmentally-relevant (nM) doses of TBT via their drinking water throughout gestation, increased fat
accumulation was detected in F1-F4 generation male descendants. Affected TBT-group males developed a
transgenerational “thrifty phenotype”: they were resistant to fat loss during fasting, rapidly gained weight when
dietary fat was increased and retained this fat even after being returned to a normal, low-fat diet. Our published
and preliminary results led us to propose a new model for transgenerational inheritance - that prenatal TBT
exposure altered higher-order chromatin structure (HOCS), changing secondary epigenetic modifiers that
inhibited expression of insulin degrading enzyme (Ide) causing diet-induced hyperinsulinemia and obesity.
Here we propose a comprehensive series of experiments designed to determine exactly how exposure of
pregnant F0 dams to TBT alters HOCS in F1-F3 primordial germ cells (PGCs), why these changes are
inherited, rather than reversed to the normal state, how these changes affect lower-level epigenetic regulators
co

## Key facts

- **NIH application ID:** 11095904
- **Project number:** 5R01ES023316-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** BRUCE  BLUMBERG; TOSHIHIRO  SHIODA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** ES
- **Fiscal year:** 2026
- **Award amount:** $633,756
- **Award type:** 5
- **Project period:** 2013-09-01T00:00:00 → 2029-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11095904

## Citation

> US National Institutes of Health, RePORTER application 11095904, Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance (5R01ES023316-13). Retrieved via AI Analytics 2026-07-01 from https://api.ai-analytics.org/grant/nih/11095904. Licensed CC0.

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