In a new study by by Walsh, McCormick, Martin, and Stocco1 of the Department of Cell Biology and Biochemistry, Texas Tech University RoundUp has just been conclusively identified as an Endocrine Disruptor.
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
Lubbock, Texas, USA
2Department of Mathematics, Texas Tech University, Lubbock, Texas, USA
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 3▀-hydroxysteroid dehydrogenase (3▀-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, 3▀-hydroxysteroid dehydrogenase, Leydig cells, Roundup, steroid hormones, steroidogenesis, steroidogenic acute
regulatory protein. Environ Health Perspect 108769-776 (2000). [Online 12
Address correspondence to D.M. Stocco, Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX
Telephone (806) 743-2505.
Fax (806) 743-2990.
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.