Roundup Inhibits Steroidogenesis by Disrupting Steroidogenic Acute Regulatory
(StAR) Protein Expression
Lance P. Walsh,1 Chad McCormick,1 Clyde Martin,2 and Douglas M. Stocco1
1Department of Cell Biology and Biochemistry, Texas Tech University Health
Sciences Center,
Lubbock, Texas, USA
2Department of Mathematics, Texas Tech University, Lubbock, Texas, USA
Abstract
Recent reports demonstrate that many currently used
pesticides have the capacity to disrupt reproductive function in animals.
Although this reproductive dysfunction is typically characterized by
alterations in serum steroid hormone levels, disruptions in spermatogenesis,
and loss of fertility, the mechanisms involved in pesticide-induced
infertility remain unclear.
Because testicular Leydig cells play a crucial role in
male reproductive function by producing testosterone, we used the mouse MA-10
Leydig tumor cell line to study the molecular events involved in
pesticide-induced alterations in steroid hormone biosynthesis. We previously
showed that the organochlorine insecticide lindane and the organophosphate
insecticide Dimethoate directly inhibit steroidogenesis in Leydig cells by
disrupting expression of the steroidogenic acute regulatory (StAR) protein.
StAR protein mediates the rate-limiting and acutely
regulated step in steroidogenesis, the transfer of cholesterol from the outer
to the inner mitochondrial membrane where the cytochrome P450 side chain
cleavage (P450scc) enzyme initiates the synthesis of all steroid hormones. In
the present study, we screened eight currently used pesticide formulations for
their ability to inhibit steroidogenesis, concentrating on their effects on
StAR expression in MA-10 cells. In addition, we determined the effects of
these compounds on the levels and activities of the P450scc enzyme (which
converts cholesterol to pregnenolone) and the 3ß-hydroxysteroid dehydrogenase
(3ß-HSD) enzyme (which converts pregnenolone to progesterone). Of the
pesticides screened, only the pesticide Roundup inhibited dibutyryl
[(Bu)2]cAMP-stimulated progesterone production in MA-10 cells without causing
cellular toxicity. Roundup inhibited steroidogenesis by disrupting StAR
protein expression, further demonstrating the susceptibility of StAR to
environmental pollutants.
Key words: chemical mixtures, cytochrome P450 side chain
cleavage, environmental endocrine disruptor, 3ß-hydroxysteroid dehydrogenase,
Leydig cells, Roundup, steroid hormones, steroidogenesis, steroidogenic acute
regulatory protein. Environ Health Perspect 108:769-776 (2000). [Online 12
July 2000]
http://ehpnet1.niehs.nih.gov/docs/2000/108p769-776walsh/abstract.html
Address correspondence to D.M. Stocco, Department of Cell Biology and
Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
79409 USA.
Telephone: (806) 743-2505.
Fax: (806) 743-2990.
E-mail: doug.stocco@ttmc.ttuhsc.edu
From:
http://www.healthlink.us-inc.com/publiclibrary/htm-data/htm-def/def189.htm
STEROID HORMONE: Fats similar to, and usually synthesized
from, cholesterol, starting with Acetyl-CoA, moving through squalene, past
lanosterol, into cholesterol, and, in the gonads and adrenal cortex, back to a
number of steroid hormones.
Nearly all of the classic hormones are proteins or
smaller peptides; they don't get inside a cell (the membrane keeps them out);
instead, they bind to, and initiate, cell changes from the outside. The
exceptions are the thyroxines (from the thyroid) and the steroid hormones.
They move into the cell, bind with receptors, and initiate changes in the way
a cell regenerates itself or synthesizes new compounds.
Because the steroid hormones stimulate cell growth,
either by changing the internal structure or increasing the rate of
proliferation, they are often called anabolic steroids.
Estrogen, an ovarian steroid, when secreted into the
bloodstream, will be bound within a short time by internal receptors inside
those cells that need estrogen for their growth; the unused portion is
partially broken down, mostly in the liver, and partially stored in a less
active form by adipose tissue.
Since luteinizing hormone from the pituitary is surged in
pulses an hour apart, the estrogen is also surged from the reacting ovaries,
and by the time more estrogen is available, the binding cells need more; their
program of synthesis has run out and needs to be started again.
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