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Environmental Factor, April 2012

Small business explores new approaches in reproductive toxicology

By Nancy Lamontagne

Cultured human Sertoli cells

Cultured human Sertoli cells, shown in this fluorescence image at 100X magnification, are a key part of the testis model. (Photo courtesy of Constance John)

Paul Turek, M.D.

Turek is the chief medical officer of MandalMed, based in San Francisco.   (Photo courtesy of Paul Turek)

Constance John, Ph.D.

John, the founder and chief executive officer of MandalMed, thinks that a functioning model of the testis could have great commercial value. (Photo courtesy of Constance John)

NIEHS grantees Paul Turek, M.D., and Constance John, Ph.D., of MandalMed Inc., are developing a human-cell based testis model to study reproductive toxicology. Such a system could provide information not available from animal studies, because of differences in how humans and animals respond to environmental exposures.

Turek and John are supported by an NIEHS Small Business Innovation Research grant, (http://projectreporter.nih.gov/project_info_description.cfm?aid=8201518&icde=11847342&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC)  which funds projects with commercial potential. John, the chief executive officer of MandalMed Inc., (http://www.mandalmed.com/MandalMed_Home.shtml)  estimates that it may take three to four years to develop a product for testing the toxicity of potential drugs in the development of sperm. “Hopefully the model can be used as an FDA-approved adjunct to animal testing during drug development,” she said.

Turek, who is MandelMed’s chief medical officer and also has a male fertility clinic in San Francisco, added, “We could discover information that tells us more about how testicular cancer or infertility begins.”

NIEHS currently supports a number of projects to develop three-dimensional human tissue culture systems to more accurately reflect in vivo responses to toxicant exposures in human tissues and organs. These models are developed using multiple cell types that replicate tissue functions more accurately than traditional cell culture systems using a single cell type. Through funding of both university and small business grants, the NIEHS has supported the development of human models of skin, eye, liver, and lung, to evaluate biological responses to a range of toxicant exposures. These efforts address goals of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods to refine, reduce, or replace animal use in toxicology testing.

Creating a functioning testis model

To create a model of the testis, the researchers will culture three types of cells in a hollow fiber. Sertoli cells, also called nurse cells, are a key component, because they support the stem cells that eventually develop into sperm, create the blood-testis barrier, and reduce the body’s immune responses to sperm. To make the model functional, the researchers will induce stem cells to differentiate into sperm inside the hollow fibers. Turek says that their work will likely provide insight that will be useful for other applications of stem cells.

If the researchers succeed in creating a functioning testis model, they can begin to examine reproductive toxicology. This will involve examining the effects of molecules, on the various cell types involved, over the 70 days it takes for sperm to develop. The analysis will take time but will provide high-quality information. “We don’t really know what the toxicology will look like,” Turek said. “We hypothesize that most effects will be on the nurse cells.”

Human challenges

Scientists have successfully produced artificial sperm, using cells from mice and other animals, but have failed to produce artificial sperm using cultured human cells. To overcome this challenge, Turek gathered experts in the various cell types and processes of spermatogenesis to be part of the research team working on the artificial testis.

John has worked extensively with human Sertoli cell cultures, which are commercially available for research applications from MandalMed’s distributor Lonza in Walkersville, Md. The team also includes Renee Reijo Pera, Ph.D., of Stanford University, who has characterized genes required to coax human embryonic stem cells into the precursors of sperm; Chuen-yan Cheng, Ph.D., of the Population Council’s Center for Biomedical Research in New York, who has shown that cadmium can destroy the blood-testis barrier; and Juan Aréchaga, Ph.D., who runs the Laboratory for Stem Cells, Development, and Cancer at the University of the Basque Country in Spain and is an expert in peritubular myoid cells, which make up the walls of the channels in the testis where sperm develop.

(Nancy Lamontagne is a science writer with MDB, Inc., a contractor for the NIEHS Division of Extramural Research and Training, Superfund Research Program, and Worker Education and Training Program.)




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