Meiosis is a key developmental process that occurs in all sexually reproducing eukaryotes, including unicellular organisms, such as the budding yeast Saccharomyces cerevisiae
. It gives rise to genetic diversity through homologous recombination between parental DNA, and it keeps chromosome numbers constant from generation to generation by creating haploid gametes. Various studies have indicated that environmental factors, such as organic solvents, heavy metals, or heat can negatively impact gametogenesis in man 
. It remains unclear, however, to what extend exposure to organic compounds (e.g.
drugs) can lead to infertility, and which specific stages of meiotic development are compromised. Such studies are difficult to conduct in humans due to ethical issues and therefore the development of experimental systems using model organisms would be beneficial.
Meiosis and sporulation in yeast and spermatogenesis in higher eukaryotes are analogous developmental pathways. Characteristic landmark events including pre-meiotic DNA synthesis, recombination, and chromosome segregation during the first and second meiotic divisions (MI and MII) are controlled in a highly similar fashion and rely on conserved genes, many of which display transcriptional up-regulation during these processes 
. These developmental stages are followed by morphogenetic differentiation events, which give rise to the formation of functional haploid gametes (commonly referred to as spores in budding yeast).
Numerous studies have demonstrated that meiotic development in yeast is coordinated at several levels including signal transduction 
, transcriptional regulation 
, meiosis-specific splicing 
, mRNA turnover 
, post-translational modification 
and degradation 
of regulatory proteins. Two nucleus-associated structures, the synaptonemal complex and the spindle-pole bodies, play important roles in coordinating proper reciprocal exchange between the homologous chromosomes during MI and packaging of meiotic products into mature gametes (reviewed in 
In addition, sporulation in yeast is also regulated on a metabolic level. In budding yeast meiotic development is induced when vegetative cells are transferred to a nitrogen-free medium containing acetate as the sole carbon source (reviewed in 
). Sporulating yeast cells undergo strong physiological changes, including a decrease in RNA and protein content, an accumulation of the storage carbohydrates 
and spore wall components 
, and a large increase in oxygen consumption. Because of the absence of external nitrogen sources, 60–70% of the pre-existing vegetative protein is degraded to generate a supply of amino acids essential for the synthesis of new sporulation-specific proteins 
Despite the aforementioned wealth of data available for regulatory mechanisms governing yeast meiosis and sporulation, currently only little is known about small molecules that have the potential to interfere with these processes. Early studies demonstrated that nitrogen-containing compounds, such as amino acids and ammonium ions prevent yeast cells from sporulating 
. Other work described the effects of chemicals that induce aneuploidy in yeast undergoing meiosis 
. Anti-neoplastic drugs, such as adriamycin, mitomycin C, and bleomycin were shown to disrupt the second meiotic division leading to the generation of diploid spores 
. These drugs, however, are not only effective during sporulation, but also abolish vegetative growth.
In this study we aimed to identify chemicals that inhibit meiotic development in yeast but do not interfere with vegetative growth. We profiled a library of 446 drugs from the NIH clinical collection with two sporulation assays, and generated sensitivity profiles of growing and sporulating cells for each of these chemicals. This approach identified 12 potent, sporulation-specific inhibitors, the majority of which are cationic amphiphilic drugs. We have studied the effects of one of these drugs, tripelennamine, on various meiotic landmarks and identified genes related to autophagy as hypersensitive to the drug using chemical genomic profiling.