Taste Gene Inactivation Causes Male Sterility, Finds Mice Study

Two proteins called TAS1R3 and GNAT3, which have been previously known to be involved in oral taste detection, also play a crucial role in sperm development, says new research published online in the Proceedings of the National Academies of Sciences.

PAS-stained paraffin section of testicular tubules from wild-type mice treated with clofibrate (Bedrich Mosinger et al)

PAS-stained paraffin section of testicular tubules from wild-type mice treated with clofibrate (Bedrich Mosinger et al)

While breeding mice for taste-related studies, Dr Bedrich Mosinger from Monell Chemical Senses Center and his colleagues discovered that they were unable to produce offspring that were simultaneously missing two taste-signaling proteins – TAS1R3 and GNAT3.

TAS1R3 is a component of both the sweet and umami (amino acid) taste receptors. GNAT3 is a molecule needed to convert the oral taste receptor signal into a nerve cell response.

The researchers determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.

This study “highlights a connection between the taste system and male reproduction. It is one more demonstration that components of the taste system also play important roles in other organ systems,” Dr Mosinger explained.

In order to explore the reproductive function of TAS1R3 and GNAT3, the team engineered mice that were missing genes for the mouse versions of the two proteins but expressed the human form of the TAS1R3 receptor – these mice were fertile.

PAS-stained paraffin sections of testicular tubules from engineered mice with blocked TAS1R3 and GNAT3 (Bedrich Mosinger et al)

PAS-stained paraffin sections of testicular tubules from engineered mice with blocked TAS1R3 and GNAT3 (Bedrich Mosinger et al)

However, when the human TAS1R3 was blocked in the engineered mice by adding the drug clofibrate to their diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm.

The sterility was quickly reversed after clofibrate was removed from the diet.

Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.

“Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor,” Dr Mosinger said, “these compounds could be negatively affecting human fertility, an increasing problem worldwide.”

“If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive,” Dr Mosinger concluded.

______

Bibliographic information: Bedrich Mosinger et al. Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility. PNAS, published online before print July 1, 2013; doi: 10.1073/pnas.1302827110