Exposure of female rats to a common fungicide causes prostate inflammation in male offspring later in life.

Sep 20, 2008

Cowin, PA, P Foster, J Pedersen, S Hedwards, SJ McPherson, GP Risbridger. 2008. Early onset endocrine disruptor induced prostatitis in the rat. Environmental Health Perspectives 116:923–929.



Synopsis by Heather Hamlin

A fungicide that blocks androgen hormone actions causes prostate inflammation in adult male rats that were exposed to the chemical before birth. This is the first study to directly link an environmental contaminant known to disrupt an androgen hormone with prostate inflammation and provides novel insight into human origins of the disease. Importantly, the inflammation patterns seen in the rats closely resemble the disease patterns seen in humans. Prostatitis is a common health problem affecting men of all ages, and the condition can lead to reproductive problems and prostate cancer. In the study, pregnant rats were exposed to vinclozolin, a commonly used fungicide, during the key time when the prostate gland develops.

Context

The prostate gland is a walnut shaped organ that sits just under the bladder in men. The reproductive organ produces 10-30% of the volume of seminal fluid, the liquid that carries sperm out of the body during ejaculation. Prostatitis occurs when the prostate becomes inflamed and swells. Problems urinating or back pain can signal the condition, which is classified as either a bacterial or nonbacterial (the more chronic) form.

Prostate inflammation affects approximately 9% of men, and accounts for about 2 million hospital visits annually. For 90% of those men, the cause of the inflammation is unknown. Over $84 billion are spent annually on prostate inflammation diagnosis and management, but since the cause is unknown, many treatments are ineffective. This study is the first to implicate fetal chemical exposure as a cause of prostate inflammation later in life.

Several groups of chemicals have the ability to disrupt the normal production and functioning of hormones. Scientists are only beginning to identify which specific compounds can disrupt fetal hormone functioning and subsequent reproductive development. Hormones regulate development of the reproductive tract. Exposures to chemicals that alter hormone function during critical times in development can lead to permanent and irreversible damage to the reproductive tract.

Vinclozolin is a fungicide used widely on food crops throughout the United States. Humans are generally exposed through food and water. Vinclozolin alters normal hormone function by competing with androgen hormones like testosterone. Many chemicals with the same effect contaminate our environment but vinclozolin is one of the few chemicals shown to modify DNA expression and lead to adverse effects for multiple generations (Skinner, 2007).

The distance from the anus to the base of the penis is termed the anogenital distance and is used as a sensitive indicator of male feminization. The shorter the distance, the more female-like the animal is perceived to be. The measurement, in humans and other animals, is used to predict infant and adult reproductive disorders. Exposure to vinclozolin is known to feminize male rats, causing female-like anogenital distances, retained nipples and various genital deformations.

What did they do?

Researchers tested how prebirth exposure to an androgen blocker affected prostate gland health and development in male rats at birth and before and after puberty. In the study, a group of pregnant female rats were fed 100 mg/kg of body weight of vinclozolin during the period of time when the male reproductive tract develops. This amount induces deformities in the male offspring's reproductive tract without being toxic to the mothers.

To evaluate hormone concentrations, researchers measured anogenital distances, examined external genitalia and sampled prostate tissue and blood from the sons at 0, 4 or 8 weeks of age.

To determine if the sons inherited Vinclozolin-altered genes, researchers examined the 113 key genes identified in the mothers as being important to inflammation and evaluated the same ones for changes in the prostate tissues of the sons.


What did they find?

At puberty, all of the male rats born to mothers exposed to vinclozolin while in the womb developed prostate inflammation. Until that time, the sons had no obvious prostate troubles. Importantly, the inflammation arising from vinclozolin exposure developed in a similar way to that seen in human adult males.

In order to function properly, the prostate must be able to respond to hormonal signals. vinclozolin reduced the ability of prostate cells to respond appropriately to androgens.

At birth, the pups exposed to Vinclozolin weighed significantly less than control pups, which were not exposed. However, these weight differences were no longer apparent by the time the pups were 28 days old.

The distance from the anus to the base of the penis was significantly shorter in all three groups of the exposed sons, indicating considerable feminization. Testis and prostate weights and testosterone concentrations were similar for both exposed and unexposed animals.

Approximately 47% of the exposed sons had deformed external genitalia and 36% had undescended testes as compared to the control animals, which had no malformations or undescended testes.

Vinclozolin was not toxic to the mother and the pregnancies were normal.


What does it mean?

These results clearly show that exposure of pregnant mothers to vinclozolin during critical times of development can lead to prostate inflammation in their adult sons. Because the pattern of disease development was similar to that seen in human males, this study could provide important insight into the development of the disease in people.

The role of environmental chemicals in the development of prostate disease has been a concern and point of controversy in the scientific community. This is the first study to directly link an environmental chemical, in this case a commonly used fungicide, as a cause of prostate inflammation.

It is known that other environmental chemicals can promote diseases, even through multiple generations. For most of these diseases, embryonic or infant exposure is necessary for the disease to develop in the parent and the symptoms to be passed on to its offspring. One example is the synthetic estrogen diethylstilbestrol (DES), which was given to pregnant women in the mid 20th Century to prevent miscarriage. An unintentional side effect occurred when the drug changed DNA patterns in a way that caused vaginal cancer in the adult daughters who were exposed in the womb. Effects are seen in granddaughters, who were never directly exposed, implying the drug's influence may be permanent.

While the exact mechanism of how vinclozolin causes prostate inflammation is still unclear, there is sufficient evidence to think that genetic changes may play a large role. Many genes that appear to be affected by the exposure were identified in the mother and sons. Past studies support these findings by showing that exposure to the fungicide changes how young or developing animals read their DNA. The permanent changes described in this previous research are transmitted through the male germline to offspring and then on to subsequent generations.

In this study, a change in the prostate tissue manifested long after the chemical exposure. Vinclozolin is changing how the DNA in the prostate is read or expressed after a certain age. If vinclozolin causes an altered reading of DNA, which leads to prostate inflammation later in life and through multiple generations, then it is important for more studies to be done to determine exactly how these changes occur.

Researchers and health care professionals need to understand how diseases such as prostatitis progress to prevent and treat them. Not understanding a disease's development is a principal reason given for the lack of effective treatments (Turner et al. 2007).

The dose of vinclozolin given to the pregnant females was significantly higher than that estimated for current human exposure. High dose experiments are commonly used to establish potential effects, because often --but not always-- high dose experiments can more powerful at discovering potential low dose effects.

Two problems arise from following this approach to detect possible risks to human health.  The first is that lower doses, within the common range of human exposure, may not be sufficient to cause the effect seen at high doses.  In the case of this experiment, this would mean that the high dose experiments inappropriately identified vinclozolin as a potential risk.

On the other hand, a substantial new body of evidence is demonstrating that high dose experiments can actually miss effects that result from lower doses.  This possibility arises because some contaminants, behaving like hormones, follow biphasic (or non-monotonic) dose-response curves (Myers and Hessler 2007).  The mechanisms producing these curves vary, but often involve the reality that the suites of genes under the hormone's (or hormone-like contaminant's) control are different at different concentrations, and that at high doses the hormone can be overtly toxic.


Resources

Gray, LE, VS Wilson, TS Stoker, C Lambright, J Furr, N Noriega, K Howdeshell, GT Ankley and LJ Guillette. 2006. Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. International Journal of Andrology 29: 96-104.

MayoClinic.com. Prostatitis.

Myers, JP and W Hessler. 2007. Does 'the dose make the poison?'

Skinner, MK. 2007. Epigenetic transgenerational toxicology and germ cell disease. International Journal of Andrology 30: 393-397.

Turner, JA, MA Ciol, M Von Korff and R Berger. 2005. Health concerns of patients with nonbacterial prostatitis/pelvic pain. Archives of Internal Medicine 165: 1054-1059.

Younglai EV, YJ Wu, WG Foster. 2007. Reproductive toxicology of environmental toxicants: Emerging issues and concerns. Current Pharmaceutical Design 13: 3005-3019.

 

News about fetal origins of adult disease

 
More news about