# Project 2: Exposomics of Endocrine Disruption

> **NIH NIH P42** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $298,583

## Abstract

PROJECT 2: SUMMARY/ABSTRACT
Arsenic, benzene, trichloroethene (TCE), formaldehyde, and polycyclic aromatic hydrocarbons (PAHs) may
have endocrine-disrupting effects at lower doses than those required for hematotoxicity or cancer induction.
There is some evidence that they can modulate steroid hormone levels in both the corticosteroid and sex
steroid pathways, potentially causing multiple adverse health effects. Here we propose to examine the
disrupting effects of these common Superfund contaminants on glucocorticoid and sex steroid hormones and
their tissue-specific effects in cell lines in vitro, mice in vivo, and perhaps most importantly in
humans with well-
characterized exposures. Endogenous cortisol is produced in response to stress and acts on the glucocorticoid
receptor (GR) triggering metabolic and other disruptions. Environmental chemicals can also impact the GR
pathway and are defined as “stressogens.” An example is arsenic, which alters GR signaling, but the
mechanisms by which this impacts different cell types expressing GR are unclear. Cumulative risk assessment
of non-genetic environmental stressors is a priority of EPA and we have developed novel approaches to do so
under the exposome paradigm. Our first central hypothesis is that arsenic is a stressogen that alters GR
activity, alone and in conjunction with other chemicals, with tissue-specific biological consequences. We
propose to use an exposomic approach to understand the dose-dependent effects of arsenic, alone and in
conjunction with other Superfund contaminants, on the glucocorticoid pathway in liver, adipocyte and blood
cells in vitro; in mice in vivo; and in exposed humans (Aims 1-3). We will use a sensitive GR activity bioassay
to screen Superfund contaminants that alter GR activity and will measure total glucocorticogenic (G) activity in
media from exposed cells and in small volumes of human plasma from subjects exposed to arsenic. Use of the
GR bioassay directly with plasma is novel. Our preliminary screening data show that arsenic is a GR
antagonist and the PAH benzo(a)pyrene, an agonist. Arsenic, as well as TCE, benzene, formaldehyde and
PAHs also cause adverse reproductive effects potentially by modulating natural estrogen and androgen sex
hormones. Thus, our second central hypothesis is that these contaminants modulate estrogen receptor (ER)
and androgen receptor (AR) activity by altering natural sex hormone levels. We will screen chemical effects on
the production of these hormones (steroidogenesis) in validated mammalian cell models, and total estrogenic
(E) and androgenic (A) activity and endogenous hormone levels in plasma from exposed populations (Aims 4-
5). Our preliminary data show that TCE increases E but not A activity in exposed males probably through
aromatase induction. Our overall goal is to understand the dose-dependent effects of key Superfund chemicals
on steroid hormone pathways, to support comprehensive and cumulative risk assessment.

## Key facts

- **NIH application ID:** 10136015
- **Project number:** 5P42ES004705-33
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** MARTYN T SMITH
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $298,583
- **Award type:** 5
- **Project period:** 1997-04-01 → 2022-08-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136015

## Citation

> US National Institutes of Health, RePORTER application 10136015, Project 2: Exposomics of Endocrine Disruption (5P42ES004705-33). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136015. Licensed CC0.

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