FYI - Short Piece - Evidence Suggesting a New Type of Endocrine Disruptor

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Research

Brief 157: SBRP Investigators Find Evidence Suggesting a New Type of

Endocrine Disruptor

Background: Recent studies have raised concerns regarding the

environmental fate of triclocarban (TCC, 3,4,4'-trichlorocarbanilide), an anti-bacterial

compound commonly added to a wide range of household and personal care

products including bar soaps, detergents, body washes, cleansing lotions and

wipes (Halden and l 2005). Drs. Jay Chen and Bill Lasley, researchers in

the UC SBRP examined TCC's endocrine-disrupting (EDS) effects using a

biomarker assay that they had created, since data on TCC's potential impact

on reproductive health are scarce and outdated.

Advances: The research group led by Drs. Chen and Lasley

investigated the EDS properties of TCC using their androgen receptor bioassay

to determine if the compound interferes with the natural action of endogenous

androgens. The cell-based androgen receptor-mediated reporting system uses

human embryonic kidney (HEK) cells lacking critical steroid-metabolizing

enzymes. The cells were transfected with an androgen receptor (AR) and a

plasmid containing a luciferase-reporting gene.

Tested alone at a concentration of 1.0 µM (~0.3 µg/mL), TCC exhibited no

significant androgenicity. However, TCC had an amplification effect on strong

native androgens such as testosterone (T), and the transcriptional activity

was time- and dose-dependent as determined by the fluorescent signal in the

androgen receptor assay.

To assess the

mechanism by which TCC mediates the enhancement of the T-signal, the

researchers added the antiandrogen flutamide to the test system. Flutamide

blocked the amplification effect of TCC, indicating that the androgen

receptor was necessary for TCC's actions. A competitive binding assay was run

on TCC with no effect, indicating that TCC does not mimic testosterone and

compete for T-binding to the AR.

The researchers'

next step was to confirm the biological relevance of the in vitro

findings by conducting in vivo studies. When castrated male rats were exposed

to TCC in combination with testosterone propionate (TP), the researchers

observed a substantial and significant increase in the weights of all

accessory sex organs compared to TCC or TP treatment alone, indicating a

synergism between TP and TCC in vivo. These data

strongly suggest that TCC has a positive androgen receptor modulatory effect

in tissues or cells that are androgen targets.

Significance: These findings suggest that TCC should be

categorized as a steroid hormone amplifier or enhancer rather than as a

simple agonist or antagonist because of the EDS property of synergism with

the native androgen hormone receptor ligand.

The amplification

effect of TCC may have an array of widespread subtle physiological

alterations in males and females. Hypothetically, amplification of androgens

by TCC at the target cell may be associated with idiopathic hyperandrogenism,

i.e., despite seemingly " normal " native circulating androgen

levels, virilization may occur. It is also conceivable that exposure to TCC

may result in defects in development or decreased reproductive function

(i.e., sperm quality) in adults. In females, increased androgenic feedback

could disrupt the normal female-specific " positive " feedback loop

associated with ovulation. Exposure to TCC may also change the balance

between estrogen signaling and androgen signaling in breast homeostasis.

Depending on the level that hormone signaling pathways are disrupted, in utero

exposure to TCC could also impair neurogenesis and sexually dimorphic

neurobehavioral development. TCC has the potential to amplify synthetic

steroidal compounds; as a result, further investigation of the interaction of

TCC with oral contraceptives, hormone replacement therapy, synthetic

androgens and glucocorticoid therapy is warranted.

Practically,

because there is no strong evidence for the improved efficacy of TCC as an

anti-bacterial agent in consumer products and as used by consumers, compared

to similar products not containing TCC, consumers may want reduce their

consumption of TCC-containing products. Likewise, its fate in the

environment, especially through the land application biosolids route, and

that of another common anti-microbial, triclosan (TCS), should be thoroughly

re-examined.

For More

Information Contact:

Bill

L. Lasley, Ph.D. (Professor Emeritus)

Department of Population Health and Reproduction, School of Veterinary

Medicine;

Department of Obstetrics and Gynecology, School of Medicine

Center for Health and the Environment

University of California,

, CA

95616-5294

Phone:

E-mail: bllasley@...

Jiangang

Chen, Ph.D.

Center for Health and the Environment

University of California,

, CA

95616-5294

Phone:

Email: jchen@...

To learn more about

this project, please refer to the following sources:

Chen J., Ahn KC,

Gee NA, Mohamed MI, Duleba AJ, Zhao L, Gee SJ, Hammock BD, and Lasley BL (In

Press). Triclocarban enhances testosterone action: A new type of endocrine

disruptor? Endocrinology. Available on the Endocrinology

web page

Chen J, Sowers MR,

Moran FM, McConnell DS, Gee NA, Greendale

GA, Whitehead C, Kasim-Karakas

SE, Lasley BL (2006). Circulating bioactive androgens in midlife women. The

Journal of Clinical Endocrinology And Metabolism 91:4387-4394.

Halden RU and l

DH (2005). " Co-Occurrence of Triclocarban and Triclosan in U.S. Water

Resources. " Environmental Science and Technology, Vol. 39:1420-1426.

Tony

.......................................................................

" Tony " Havics,

CHMM, CIH, PE

pH2, LLC

5250 E US 36, Suite 830

Avon, IN

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