Rats are fat after long-term exposure to lower levels of atrazine.

Apr 23, 2009

Lim S., SY Ahn, IC Song, MH Chung, HC Jang, KS Park, KU Lee, Y Pak and HK Lee. 2009. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. Public Library of Science, one doi:10.1371/journal.pone.0005186.



Synopsis by Heather Hamlin

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A new study with rats shows that long-term exposure to the common agricultural pesticide atrazine causes weight gain in animals fed normal diets and obesity in those fed high fat diets. These health conditions can lead to diabetes, and they may be triggered by damage to critical structures in cells responsible for making energy. The new results suggest a mechanism to explain prior studies that found an association between areas of the United States with heavy atrazine use and high obesity prevalence. 

 

Context

Glucose is a sugar produced from the breakdown of food and is the body’s main source of energy. Glucose in the blood is commonly referred to as “blood sugar” and in order to be useful, it needs to be able to get into the body’s cells.

Insulin is a hormone produced by the pancreas that helps glucose get into the body’s cells.

Insulin resistance is a condition in which insulin is produced, but the body’s cells don’t use it to help glucose gain entry into cells like they should. The pancreas responds by producing even more insulin.

Eventually, glucose builds up in blood. Therefore, people with insulin resistance often have high levels of glucose in their blood. Excess blood sugar increases the chances of developing type II diabetes and is a key component of pre-diabetes.

Mitochondria are structures in cells that produce energy. Often called the “powerhouse” of the cell, mitochondria use glucose and other substances to produce energy to support the body’s functions.

Studies have shown that improperly functioning mitochondria can lead to insulin resistance (Petersen et al. 2003).

Atrazine is a pesticide widely used in the United States for the control of weeds in agriculture. The chemical can taint surface and groundwater, especially in highly farmed areas, such as the Midwest and California. There is an association between areas of the United States where atrazine is heavily used and the prevalence of obesity.

Atrazine can affect the health of animals. Laboratory and field studies have found reproductive and developmental problems associated with exposure to the chemical. In frogs, atrazine has been shown to cause significant gonadal abnormalities at concentrations 30 times less than the drinking water standard of 3 parts per billion (ppb) (Hayes et al. 2002).

People are exposed to atrazine through drinking contaminated water, direct contact and inhalation.  More than 19 million people drink atrazine contaminated tap water in the US. Atrazine in the tap water of more than 7 million Americans has been measured above health based limits set for the herbicide (Environmental Working Group).

What did they do?

This study was undertaken to determine if atrazine could be contributing to the obesity epidemic and to attempt to determine the mechanisms involved.

Researchers exposed a group of rats to the pesticide atrazine in their drinking water. The rats received one of two concentrations of atrazine (30 micrograms per kilogram and 300 micrograms per kilogram) for 5 months. These concentrations are higher than US drinking water limits but well within the range of what has been measured in surface and groundwater in areas with high atrazine use (Hayes et al. 2002). 

Another group of rats, the control group, received no atrazine in their drinking water.

Some rats in both the treatment and the control groups received a normal rat diet for the entire 5 months. Other rats received a normal diet for the first 3 months, then were fed a high fat diet for the last two months of the study.

Researchers measured the activity level of the rats throughout the study by using a machine that periodically monitored their movement patterns.

At the end of the study, the rats were weighed and their body fat percentages were determined. Concentrations of glucose and insulin in the blood of the rats was measured. Other tests of pancreatic function and insulin resistance were also performed.

The structure of the rat’s mitochondria in liver and muscle cells was observed with a high power microscope. Tests of mitochondrial activity were also performed.


What did they find?

For the first few months, atrazine exposed and control rats fed the normal diet weighed the same.

By the end of the study, however, the rats fed the normal diet that were exposed to atrazine in their drinking water were about 5 percent heavier than the unexposed rats. Rats exposed to atrazine that were fed the high fat diet were about 10 percent heavier than unexposed rats fed the same high fat diet.

There were no differences in food intake or activity level between the groups of rats.

Visceral fat, or the fat that surrounds the body’s organs, as well as fat within the organs themselves was the reason for the excess weight.

Rats exposed to atrazine were more insulin resistant and levels of both glucose and insulin were significantly higher than unexposed rats.

The mitochondria of atrazine exposed rats were swollen and parts of them were partially destroyed.

Tests of mitochondrial activity showed that atrazine directly impaired the functioning of the mitochondria.


What does it mean?

This study showed that low dose exposure to atrazine caused significant weight gain and insulin resistance in rats. Both conditions can lead to diabetes, which is a major health problem in the US.

This study highlights the importance of understanding the effects that environmental pollutants, such as pesticides, may have in the development of human diseases and disorders.

Additionally, this is the first time researchers describe how an environmental contaminant, in this case atrazine, can disrupt mitochondrial function and possibly lead to insulin resistance. Previous studies have described a close association between improper mitochondrial function and insulin resistance in humans, the precursor for diabetes.

Since mitochondrial functioning and diabetes is similar for rats and humans, the results of this study may apply to people as well.

Past studies have shown that rats exposed to 10 to 100 fold higher concentrations of atrazine lost weight. In this study, the rats were  exposed to lower levels of atrazine over a long period and the animals gained weight. The rats fed a normal diet gained approximately 5 percent more weight than unexposed rats. Rats fed a high fat diet gained almost 10 percent more weight than the unexposed animals. This pattern, high dose causes weight loss while low dose cause weight gain, is an example of a non-monotonic dose response curve, in which high dose experiments do not predict low dose results. Findings like this invalidate a key assumption-- "the dose makes the poison"-- used to justify current procedures for setting exposure safety standards.

The authors interpret this difference to mean that "acute exposure to high concentrations of ATZ is toxic, and thus prevents weight gain and possibly causes weight loss. In contrast, chronic low-dose ATZ exposure might lead to mild mitochondrial damage that mimics the characteristic of the insulin-resistance state, and hence, leads to weight gain."

If this held true for people, a 150 pound person exposed to low doses of atrazine eating a high fat diet would gain nearly 15 more pounds than someone else who was not exposed to atrazine but who ate the exact same foods.

The increases in weight were due to increases in fat and not due to beneficial increases such as increased muscle mass. This excess fat was found around the internal organs as well as in the organs themselves. Since the atrazine exposure caused the rats to gain weight without a change in food intake or exercise, researchers speculate that the pesticide lowered the metabolism of the mice.

Excess fat in humans is currently an epidemic problem in the United States and is associated with cardiovascular disease, diabetes and a host of other problems.

While concentrations of atrazine used in this study were below drinking water limits of 3 micrograms per liter, the low dose concentration in this study was over 10,000 times less than the dose required to cause reproductive effects in other rat studies and is in range with doses required to promote cancer in human cells (Wetzel et al. 1994; Sanderson et al., 2000).

The rats exposed to atrazine were more insulin resistant than unexposed rats and had significantly more glucose and insulin in their bloodstreams. Insulin resistance is a primary precursor for diabetes.

Diabetes and obesity are major health concerns that are increasing at alarming rates in the United States and other developed countries. It is thought that this rapid increase cannot be explained by genetics alone and environmental factors are contributing to the rise.


Resources

Hayes TB, A Collins, M Lee, M Mendoza, N Noriega, AA Stuart and A Vonk 2002. Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses. Proceedings of the National Academy of Sciences 99:5476-5480.

National Tap Water Database. Environmental Working Group.

Petersen KF, D Befroy, S Dufour, J Dziura, C Ariyan, DL Rothman, L DiPietro, GW Cline and GI Shulman 2003. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140-1142.

Sanderson JT, W Seinen, JP Giesy and M van den Berg 2000. 2-chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells: A novel mechanism for estrogenicity? Toxicological Sciences 54:121-127.

Wetzel LT, LG Luempert, CB Breckenridge, MO Tisdel, JT Stevens, AK Thaker, PJ Extrom and JC Eldridge 1994. Chronic effects of atrazine on estrus and mammary-tumor formation in female Sprague-Dawley and Fischer-344 rats. Journal of Toxicology and Environmental Health 43:169-182.

 

 

 

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