Developing a human-based stem cell model for reproductive toxicity

Introduction

Environmental factors and chemicals are thought to be one cause of declining male fertility. Reproductive toxicity is becoming a major public health problem. Currently, new pharmacological or chemical compounds are tested in animals for their effects on reproduction before entering the market. This risk assessment is essential but time-consuming, expensive, and is not always predictive in humans since animals have different reproductive characteristics and physiology. A validated and qualified human system to assess reproductive toxicity would be invaluable in addressing this conundrum between regulatory requirements and true relevance.

Project Overview

Through my ERC-CoG, I have built a large repository of knowledge and developed robust technology on human in vitro gametogenesis, more specifically on how to generate male gamete progenitors from human pluripotent stem cells. This, together with my bioinformatics know-how, makes me exceptionally well-placed to optimize a human-based high-throughput screening assay for male reproductive toxicity for use by the private sector in filing reproductive safety data to the regulatory authorities.

ReproTox Assay Development

This ReproTox assay will be further optimized by:

1. Increasing throughput
2. Standardizing measurements

Additionally, it will be integrated with a software innovation, including a machine learning algorithm to automate quantification and a web tool. Before we carry out a pilot screen using FDA-approved spermatotoxic compounds, we will conduct market research to define the commercialization route.

Expected Outcomes

Reducing the number of compounds that show male reproductive toxicity at very early stages of drug development will contribute to an effective first-tier toxicity screening. This will not only provide standard protocols for:

• Quantitative
• Rapid
• Cost-effective
• High-throughput
• Scalable
• Reproducible toxicity testing

But also reduce, and perhaps eventually replace, animal use. ReproTox will ultimately lead to economic, societal, environmental, health, and ethical benefits.