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Zhang, S-Y, Y Ito, O Yamanoshita, Y Yanagiba, M Kobayashi, K Taya, C-M Li, A Okamura, M Miyata, J Ueyama, C-H Lee, M Kamijima and T Nakajima. Permethrin may disrupt testosterone biosynthesis via mitochondrial membrane damage of leydig cells in adult male mouse. Endocrinology, in press. |
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The widely-used synthetic insecticide permethrin dramatically reduces testosterone levels and sperm counts in adult male mice exposed to it for six weeks. Permethrin causes reproductive damage by altering the beginning steps of testosterone synthesis in the testes, lowering testosterone production.
Compared to untreated mice, animals exposed to the highest levels of the common pesticide had 75% less hormone in the testes and 90% less in the blood, while sperm counts were halved. This study confirms past results and identifies a mechanism via which synthetic pyrethroids -- like permethrin, which is used in homes and agriculture and found in house dust and food -- reduce male reproductive hormone levels and affect sperm numbers and motility. |
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Permethrin is widely used in consumer products to kill or repel insects. |
Context: Testosterone levels and sperm counts in men have reportedly declined during the last 20 and 80 years, respectively (Travison et al. 2007, Swan et al. 2000). From the late 1980s until 2004, blood testosterone levels dipped about 1% per year in men between the ages of 45 and 80. Sperm counts fell about 1.5% per year in the US and about 3% per year in Europe/Australia but stayed about the same in non-Western countries between the 1930s and the 1990s. Environmental chemicals are suspected of playing a role in these declines (Swan et al. 2003).
Testosterone is a sex hormone required for development of male secondary characteristics and for normal sperm production in mammals. Testosterone is made in the testes from cholesterol (a type of fat molecule). The first step is to move cholesterol into the cell's mitochondria , the energy generating organelle located in a cell's liquid cytoplasm. A protein called steroidogenic acute regulatory protein (StAR) escorts cholesterol across the mitochondria's membrane. An enzyme called cytochrome P450 side-chain cleavage (P450scc) converts cholesterol into pregnenolone. A series of steps controlled by other enzymes change pregnenolone into testosterone.
Permethrin is a synthetic pyrethroid insecticide used worldwide to control insects. The artificial pyrethroids are neurotoxins patterned after the natural chemical pyrethrin that is found in chrysanthemums. The long-lasting synthetics prefer fat to water and this makes the chemicals likely to accumulate in animal and human tissues. Of the four different types, or isomers, the cis-permethrin form is the most toxic and effective insecticide.
Pyrethroids interfere with the nervous system by changing how sodium is moved into and out of cells. The change triggers nerve cells to continuously react, creating tremors, aggressive behavior and uncoordinated movements. Although the chemical is intended to kill invertebrate pests, the insecticide is toxic to bees and other beneficial insects, too. It is considered a human carcinogen and proven endocrine disruptor that has known adverse effects on the nervous, immune and reproductive systems of animals.
Annual 2004 global sales of permethrin were about $50 million and annual US production is estimated to be greater than one million pounds (ATSDR). The versatile insecticide is used in homes, yards and gardens to control pests such as ticks, mosquitoes, human head lice, scabies, and fleas on dogs, cats and other pets. It is also widely used in agriculture and forestry. Adults and children are exposed to the neurotoxin in yards, inside homes and on food, where it is commonly detected. |
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What did they do? Zhang et al. exposed adult male mice to three doses of permethrin (0, 35 or 70 milligrams/kilogram) for 6 weeks. At the end of the month and a half exposure, they measured blood and testicular testosterone levels, sperm count and quality, steroid synthesis enzyme expression levels and reproductive organ weights.
What did they find? The 6-week exposure to 35 or 70 mg/kg cis-permethrin reduced sperm counts in both treatment groups by 30 and 45%, respectively (graph below). Sperm motility was reduced by 25 and 35%, respectively, in the treated groups.
Testicular testosterone production was decreased 50 and 75% respectively (graph below). The level of testosterone in blood was decreased 70 and 90%, respectively.
Luteinizing hormone (LH) is released by the body and acts on the testes to increase testosterone production. As the level of testosterone falls, more LH is released in an attempt to stimulate testosterone production. In this study, permethrin resulted in a significant increase in LH of 500% and 1,000%, respectively.
A significant correlation was observed between testosterone levels and cis-permethrin residues in individual mice testes after exposure (r2=0.88). That is, as the level of permethrin went up in the testis, the level of testosterone went down.
No significant changes were observed in body, reproductive organ weights, and sperm morphology after cis-permethrin treatment. This shows that permethrin's effects on testosterone and sperm were not due to a general toxic effect of the chemical.
In order to find a potential cause for the decreased sperm count and testosterone level, Zhang et al. examined the expression of several genes necessary for testosterone synthesis. Gene expression is the first step in protein synthesis.
Permethrin exposure significantly diminished the testicular mRNA and protein expression levels of StAR protein and P450scc enzyme. These two proteins are required for the first steps in testosterone production.
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Leydig cells, located in the testes, manufacture sperm. In treated mice, the membrane surrounding the mitochondria inside these important cells was damaged. The authors suggest that the "insecticide permethrin may cause the mitochondrial membrane impairment in Leydig cells and disrupt testosterone biosynthesis by diminishing the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone in the cells, thus reducing subsequent testosterone production."
What does it mean? Testosterone levels and sperm counts have declined in men over the last 25 to 80 years. Endocrine disrupting chemicals have been implicated in this decline. Humans are exposed to a wide variety of chemicals that in concert function to decrease androgen action and potentially decrease fertility.
This study concludes that one of the more commonly used insecticides, permethrin, affects the adult male reproductive system in ways that interfere with normal testosterone production. Exposure to relatively high amounts (but well below toxic levels that would kill rodents) of the insecticide decreases testosterone levels in the testes and blood, increases blood levels of the signaling luteinizing hormone, alters mitochondrial membranes in Leydig cells, changes gene expression controlling important proteins and reduces sperm health and numbers.
The results are similar to past studies that have looked at effects of other related pyrethroid pesticides on the male reproductive system. This study also provides further information about how the chemical alters cell functions to interfere with testosterone production that leads to lower hormone levels in the blood and testes. The study is the first to "demonstrate that cis-permethrin exposure mainly induced Leydig cell mitochondrial membrane damage and disrupted the limiting steps of the steroidogenic process."
Permethrin is commonly used inside the house and on pets so people who regularly use the insecticide -- and their children -- may also breathe and eat the chemical.
While the doses used in this study were high, the effects on testosterone levels, StAR gene expression and sperm count were profound. The authors state that "the dose of human occupational exposure was roughly estimated to be 0.12 mg/kg (unpublished data) about 100 times lower levels than the exposed mice on a weight basis."
Importantly, all of the doses tested resulted in decreased testosterone and sperm count. It is very likely that lower exposure levels would have similar, but perhaps less dramatic, negative effects.
It is also important to note that these effects were observed in adult mice. Fetal and young mice are highly likely to be much more sensitive to the effects of permethrin. Their developing reproductive tract depends upon appropriate levels of testosterone to develop normally. This study suggests low levels of permethrin may be dangerous for developing organisms.
Further, StAR expression is necessary to move cholesterol across the mitochondrial membrane as the first step in steroid synthesis. Although the current study did not examine the effects of permethrin in females, it is likely that the level of other steroid hormones, such as estradiol, may be reduced by this insecticide.
Resources:
Agency for Toxic Substances and Disease Registry (ATSDR). 2003. Production, import/export, use, and disposal. In Toxicological profile for Pyrethrins and Pyrethroids. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
Cox, Caroline. 1998. Permethrin Insecticide Factsheet. Journal of Pesticide Reform. 18(2):14-20.
e.hormone. The hormones: Androgens.
Swan, SH, EP Elkin and L Fenster, 2000. The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996. Environmental Health Perspectives 108(10): 961-6.
Swan, SH, RL Kruse, F Liu, DB Barr, EZ Drobnis, JB Redmon, C Wang, C Brazil and JW Overstreet. 2003. Semen quality in relation to biomarkers of pesticide exposure. Environmental Health Perspectives 111(12):1478-84.
Travison, TG, AB Araujo, AB O'Donnell, V Kupelian and JB McKinlay. 2007. A population-level decline in serum testosterone levels in American men. Journal of Clinical Endocrinology and Metabolism 92(1):196-202.
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