Atrazine acts in the brain to disrupt the hormones that trigger ovulation.

Aug 20, 2009

Foradori, CD, LR Hinds, WH Hanneman and RJ Handa. 2009. Effects of atrazine on GnRH neuroendocrine function after its withdrawal in the adult female Wistar rat. Biology of Reproduction doi:10.1095/biolreprod.109.077453.




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The common and highly-used herbicide atrazine can act within the brain to disrupt the cascade of hormone signals needed to initiate ovulation, finds a study with rats published online in the journal Biology of Reproduction. Ovulation is a complex process that begins in the brain and ends with the release of eggs from the ovary. This new study finds that exposure to atrazine can interrupt this process but once the exposure ends, normal function resumes in a few days. The results shed new light on the way atrazine affects the female reproductive system and the persistence of these effects when adults are exposed.

 

Context

Atrazine is one of the most commonly used herbicides in the the US and the world. More than 76 million pounds are used on US fields each year, particularly in the Central Plains.

Its primary use is to control weeds in agricultural fields, but it is also applied by certified professionals on golf courses, athletic fields and lawns. Stormwater, irrigation and wind can carry the herbicide off of fields where it can taint groundwater and surface water.

Wildlife and human exposure is likely due to its heavy use, especially during springtime planting season. People can be exposed through drinking water and the air, if breathed in during or right after application.

Laboratory and wildlife studies show that atrazine can cause reproductive and other organ abnormalities in vertebrates. As a potential endocrine disruptor, the herbicide can affect how gonads form in developing frogs, even at low doses. It induces a range of reproductive changes in other vertebrates as well, including rodents. These findings suggest that atrazine may also be an endocrine disruptor in humans.

The most persistent effects of atrazine occur when exposure occurs during development – rather than in adulthood – because the brain and reproductive organs are still forming. Effects of developmental exposure are less likely to be reversible.

Atrazine was banned in the European Union in 2004. The US Environmental Protection Agency’s Office of Pesticide Programs has concluded that atrazine is safe when used as indicated on the label.

In mammals, ovulation – the release of an egg from the ovaries – is a complex process that requires precise communication via hormone signals between the brain and the ovary. The hormone signaling system is similar in rats and humans.

As the time of ovulation approaches, neurons within the brain that generate a hormone called gonadotropin releasing hormone (GnRH) become active and signal the pituitary gland to release luteinizing hormone (LH). This surge of LH then stimulates the ovary to ovulate.

What did they do?

The study used rats whose ovaries were surgically removed. The female rats were given the hormones estrogen and progesterone to stimulate the release of two important hormones needed for ovulation: gonadotropin releasing hormone (GnRH) from the brain and luteinizing hormone (LH) from the pituitary gland.

The rats were then fed atrazine daily for four days to see if the herbicide could interfere with the release of GnRH and LH. The doses were higher than would be considered relevant for humans but are within the range of what previous studies have used in similar animal studies. Doses given were 0, 50, 100 or 200 milligrams per kilogram (mg/kg) of body weight.

What did they find?

GnRH activity and LH levels were significantly lower in animals fed atrazine, regardless of dose.

When the herbicide exposure was stopped, LH levels returned to normal within four days.

These results suggest that the reproductive effects of adult exposure to atrazine are reversible.

What does it mean?

Exposure to atrazine reduces the activity of the GnRH neurons in the brain and blocks the LH surge that controls ovulation in vertebrates.

The hormone pathways return to normal when the herbicide exposure is stopped.  This means that atrazine acts on the brain to impact the capacity to ovulate.

This study looked at the effect of adult exposure. Normal hormone function resumed within a few days once the exposure ended, suggesting that the impact is reversible. Exposure during development may produce different longer-lasting or permanent results.

Collectively, the results of this study – along with a prior study by the same research group – demonstrate that exposure to atrazine in adults can disrupt the surge of hormones needed to trigger ovulation in rats. This mechanism is similar in rats and humans, suggesting that disruption in humans is at least possible.

“We were particularly surprised by how quickly the animals were able to recover after atrazine withdrawal,” says lead author Chad Foradori via e-mail correspondence. “But perhaps we should not have been because previous work from other laboratories have shown that atrazine is cleared from the blood and brain of the rodent by 24 hours.” 

This is one of the first studies to show that this complex signalling pathway resumed normal function so quickly. It remains to be determined if similar effects of acute atrazine exposure occur in animals whose gonads have not been removed or in humans.

The impact of atrazine exposure on the development and function of the reproductive system has historically been controversial. Some of the earliest studies to look at this issue found evidence for abnormalities in frogs. More recent studies have documented effects in mammals as well.

In 2004, partially as a result of this evidence, the European Union banned the use of atrazine. Currently, the US Environmental Protection Agency considers the animal data to be insufficient to determine if atrazine could cause reproductive problems in humans.

“These findings suggest to us that atrazine’s primary site of action is the brain but its inhibitory effects are transient in nature” said Foradori.


Resources

Atrazine. 2007. Agency for Toxic Substances and Disease Register.

Conception and Fertility: What Happens During Ovulation? Ovulation-calculator.com.

Cooper, RL, SC Laws, PC Das, MG Narotsky, JM Goldman, EL Tyrey, TE Stoker. 2007. Atrazine and reproductive function: mode and mechanism of action studies. Biology of Reproduction 80:98-112.

EU on Atrazine. Living on Earth Week of April 21,2006 .

Foradori CD, LR Hinds, WH Hanneman, ME Legare, CM Clay, and RJ Handa. 2009. Atrazine inhibits pulsatile luteinizing hormone release without altering pituitary sensitivity to a GnRH receptor agonist in female wistar rats. Biology of Reproduction 81:40-45.

Hayes T, K Haston, M Tsui, A Hoang, C Haeffele and A Vonk. 2002. Herbicides: Feminization of male frogs in the wild. Nature 419: 895-896.

McMullin TS, JM Brzezicki, BK Cranmer, JD Tessari and ME Andersen. 2003. Pharmacokinetic modeling of disposition and time-course studies with [14C]atrazine. Journal of Toxicology and Environmental Health A. 66(10):941-64

 

 

 

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