Abstract
Meiosis is a highly regulated developmental process that occurs in all eukaryotes that engage in sexual reproduction. Previous epidemiological work shows that male and female infertility is rising and environmental factors, including pollutants such as organic solvents, are thought to play a role in this phenomenon. To better understand how organic compounds interfere with meiotic development, the model organism Saccharomyces cerevisiae was exposed to 446 bioactive molecules while undergoing meiotic development, and sporulation efficiency was quantified employing two different high-throughput assays. 12 chemicals were identified that strongly inhibited spore formation but did not interfere with vegetative growth. Many of these chemicals are known to bind to monoamine-receptors in higher eukaryotes and are cationic amphiphilic drugs. A detailed analysis of one of these drugs, tripelennamine, revealed that it induces sporulation-specific cytotoxicity and a strong inhibition of meiotic M phase. The drug, however, only mildly interfered with pre-meiotic DNA synthesis and the early meiotic transcriptional program. Chemical-genomic screening identified genes involved in autophagy as hypersensitive to tripelennamine. In addition, we found that growing and sporulating yeast cells heterozygous for the aminophospholipid translocase, NEO1, are haploinsufficient in the presence of the drug.
Highlights
Meiosis is a key developmental process that occurs in all sexually reproducing eukaryotes, including unicellular organisms, such as the budding yeast Saccharomyces cerevisiae
Decreasing fluorescence intensities were indicative of decreasing sporulation efficiency as determined by microscopy (0%, 13%, 56%, and 98% spores were observed after 24 hours at 2 mM, 1 mM, 0.5 mM and 0 mM ammonium sulfate, respectively)
A strong over-representation of genes involved in vacuolar transport (p-value: 2.96 * 10216) and autophagy (p-value: 1.19 * 10211) (ATG1, ATG2, ATG3, ATG7, ATG9, ATG10, ATG13, ATG16, ATG18, IRS4, MON1, TRS85, VPS30) was found. These data suggested that a dysfunctional autophagy pathway contributes to TA toxicity. This observation is in line with a recent study demonstrating that yeast cells treated with sertraline, which like TA is a cationic amphiphilic drug, accumulates incompletely digested autophagosomal intermediates [40]
Summary
Meiosis is a key developmental process that occurs in all sexually reproducing eukaryotes, including unicellular organisms, such as the budding yeast Saccharomyces cerevisiae. Various studies have indicated that environmental factors, such as organic solvents, heavy metals, or heat can negatively impact gametogenesis in man [1,2] It remains unclear, to what extend exposure to organic compounds (e.g. drugs) can lead to infertility, and which specific stages of meiotic development are compromised. 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 [3,4,5] 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)
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