Abstract
To measure the testicular toxicity of two fungicides (carbendazim and iprodione), alone or in a mixture, we used a rat ex vivo model of seminiferous tubules, greatly reducing the number of rodents used, in accordance with the 3R rule (Replacement, Reduction, and Refinement). This model allows the representation of puberty, a critical life period with regard to endocrine disruptors. The cellular modifications were followed for three weeks through transcriptomic and proteomic profiling analysis. A quantitative and comparative method was developed to estimate how known pathways were disturbed by each substance. This pathway-driven analysis revealed a strong alteration of steroidogenesis and an impairment of meiosis in all cases, albeit the initial molecular events were different for both substances. The ex vivo cytogenetic analysis confirmed that both fungicides alter the course of the first meiotic prophase. In addition, the mixture of both substances triggered effects greater than the sum of their cumulative effects and compromised future sperm motility after a shorter time of exposure compared with the fungicides tested separately. The alliance of an ex vivo culture with omics strategies complemented with a physiological examination is a powerful combination of tools for testing substances, separately or in a mixture, for their testicular toxicity. In particular, proteomics allowed the identification of systematically differentially expressed proteins in the secretomes of exposed cultures, such as FUCO and PEBP1, two proteins linked with the motility and fertilizing ability of spermatozoa, respectively. These proteins may be potential biomarkers of testicular dysfunction and infertility.
Highlights
The recent awareness of the residual presence in foods, wines and drinking water of many pesticides requires urgent investigation of their potential toxicities to human health and the environment
The number of transcripts differentially expressed by treated cultures compared with untreated cultures reflects the magnitude of the cellular disruption
4.7 Concluding remarks In the current study, omics tools enabled the comparative analysis of multiple doses and times of exposure, identifying the molecular mechanisms of action of substances while pointing to potential biomarkers
Summary
The recent awareness of the residual presence in foods, wines and drinking water of many pesticides requires urgent investigation of their potential toxicities to human health and the environment. Since the middle of the twentieth century in developed countries, studies have reported a significant decrease in human fertility associated with lowered sperm quality and an increase in reproductive diseases such as testicular and ovarian cancers (Jensen et al, 2002). Abbreviations EDC, endocrine disrupting chemical; CBZ, carbendazim; ER, endoplasmic reticulum; IPR, iprodione; CCK, cocktail or equimolar mixture of carbendazim and iprodione; BTB, blood-testis barrier; FC, fold change; SC, synaptonemal complex; PI, pachytene index; L/Z, leptotene/zygotene transition
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