Diabetes Drug Makes Male Minnows More Female

Male minnows exposed to a widely used diabetes drug ubiquitous in wastewater effluent had feminized reproductive parts and were smaller and less fertile, according to a .

It is the first study to examine the drug metformin’s impact on fish endocrine systems and suggests that non-hormone pharmaceuticals pervasive in wastewater may cause reproductive and development problems in exposed fish.

Metformin is largely used to combat insulin resistance associated with type-2 diabetes, which accounts for about 90 percent of all diagnosed U.S. adult diabetes cases.

Researchers from the University of Wisconsin-Milwaukee exposed young fathead minnows to water containing levels of metformin commonly found in wastewater effluent. Eighty-four percent of 31 metformin-exposed male fish exhibited feminized reproductive organs.

“Normally in females you see eggs developed in ova, in males, you see a different structure – producing tiny sperm instead of an egg structure,” said Rebecca Klaper, an associate professor at the University of Wisconsin-Milwaukee and senior author of the study. “We saw development of larger egg structures within the [male’s] testis.”

A couple of non-exposed males had very minor feminization, but signs of egg development were nothing compared to what happened in the exposed fish, Klaper said. In addition to the feminization, exposed male minnows weighed less and had significantly less babies when they reproduced, suggesting that the feminization may impact their ability to reproduce properly.

Pharmaceutical chemicals are ubiquitous in wastewater effluent. Researchers estimate that, by mass, metformin is among the  in wastewater. 

More than nine percent of the U.S. population has diabetes, according to the Centers for Disease Control and Prevention. The agency estimates that from 1980 to 2011, cases of diagnosed diabetes almost tripled.

Increased illnesses means more drugs. Pharmaceutical drugs get into our wastewater when people flush their medication or, more commonly, when they excrete them. Metformin, unlike many pharmaceutical drugs, is not metabolized by the human body, and gets excreted unchanged.

Metformin’s “really been hitting people’s radar more of late,” said Dana Kolpin, a U.S. Geological Survey research hydrologist based in Iowa and project chief of the agency’s emerging contaminants project. Kolpin said as water testing methods have gotten more sophisticated, metformin seems to be one of the most frequently detected. “It’s persistent and mobile,” he said.

Scientists have expressed concern that birth control and other hormone mimicking drugs in water could impact fish populations and cause feminization. Last year U.S. Geological Survey  intersex fish in Pennsylvania’s Susquehanna, Delaware and Ohio river basins, suggesting that estrogenic chemicals were to blame. 

However, metformin is not an estrogenic or hormone-mimicking drug. Rather it is designed to improve insulin sensitivity. It appears a “nontraditional endocrine disrupting chemical,” Klaper and her University of Wisconsin-Milwaukee colleague, Nicholas Niemuth, wrote in the study published in the journal Chemosphere.

While researchers are not totally clear how the drug disrupts fish hormones, metformin has been shown to alter the activity of certain enzymes that are involved in hormone pathways.

“We know from some vertebrate studies that insulin and metabolism in an organism is tied into reproduction,” Klaper said. “But how metformin would cause a difference in actual egg production is something we don’t know but is very interesting. Now we’re trying to figure out why.”

Klaper previously found that metformin caused some signs of endocrine disruption when she exposed adult fish to the drug for 28 days. However, no intersex tissue was found, suggesting that exposure during development might be the major concern.

It’s not clear if all fish would react to metformin exposure as the fathead minnows did, Kolpin said. Klaper said the development of male and female fish is not entirely the same across species. She said they would continue testing fathead minnows and also look at zebrafish to see if they exhibit similar impacts.

Kolpin said some waterways also have been shown to have a metformin transformation compound, called guanylurea, which is formed when metformin comes in contact with bacteria such as in sewage.

“It’ll be worth finding out if its transformation product also has these bioactive properties,” Kolpin said.

The U.S. Environmental Protection Agency’s latest —water pollutants not subject to regulations yet but that might render water unsafe—includes several pharmaceuticals that act on hormones. Metformin is not on the list, published in February.

Klaper and Niemuth wrote that metformin would probably not show up as an endocrine disruptor under the current testing used by the U.S. EPA Agency, which relies on the binding of chemicals to hormone receptors. Structurally, metformin doesn’t resemble hormones. The results, they argue, suggest the EPA should broaden its testing.

“Given its environmental persistence and presence worldwide, this compound merits further research on its potential environmental impacts as well as its impacts on vertebrate development more generally and should be added to the list of potential EDCs [endocrine disrupting chemicals],” Klaper and Niemuth wrote.

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