Abstract
The genotoxic and nephrotoxic mycotoxin Ochratoxin A (OTA) has also been reported to have adverse effects on oocyte maturation and embryo development. Previous studies on the effects of OTA on female fertility have used micromolar concentrations, but no information is available to date on effects in a more relevant nanomolar range. This study used a juvenile sheep model to evaluate the effects of oocyte exposure to low levels of OTA on maturation, fertilization, and embryo development. Further, it was investigated whether different mechanisms of action of OTA could be responsible for varying toxic effects at different levels of exposure. Cumulus-oocyte-complexes (COCs) were exposed to 10 μmol/L–0.1 nmol/L OTA during in vitro maturation and evaluated for cumulus viability, oocyte maturation, and bioenergetic/oxidative status. COCs were subjected to in vitro fertilization, embryo culture, and embryo quality assessment via morphology, viability, bioenergetic/oxidative status, and time-lapse monitoring. At micromolar concentrations, OTA induced cytotoxic effects, by reducing cumulus expansion and oocyte maturation. OTA altered temporospatial dynamics of zygote pronuclear formation and embryo morphokinetics. Blastocysts, even morphologically normal, were found to undergo collapse events, which were probably related to boosted blastocyst mitochondrial activity. At nanomolar concentrations, OTA did not affect COC morpho-functional parameters, but impaired oocyte ability to prevent polyspermy and increased blastocyst apoptosis. In conclusion, in the female germ cell, cytotoxic nonspecific effects characterize OTA-induced toxicity at high exposure levels, whereas fine tuning-mode effects, not associated with altered cell viability and integrity, characterize OTA toxic action at low levels.
Highlights
Ochratoxin A (OTA) is a naturally occurring mycotoxin produced, as a secondary metabolite, by several fungi of Aspergillus and Penicillium genera (Malir et al 2016)
Representative photomicrographs of OTA-induced inhibition of cumulus expansion and apoptosis are provided in Online Resource 2 whereas Online Resource 3 shows OTAdependent oocyte chromatin configurations
(*) Data are referred to meiotic spindle (MII) oocytes from Table 1 Chi Square test: Comparisons OTA-exposed versus vehicle control (1%MeOH): a, e = p < 0.0001
Summary
Ochratoxin A (OTA) is a naturally occurring mycotoxin produced, as a secondary metabolite, by several fungi of Aspergillus and Penicillium genera (Malir et al 2016). Inhibition of protein synthesis and energy production, induction of oxidative and nitrosative stress, DNA adduct formation, as well as apoptosis/necrosis induction, and cell cycle arrest have been reported (Kőszegi and Poór 2016; Tao et al 2018). The association between oxidative stress and the loss of mitochondrial membrane potential with apoptosis produced by OTA was noted in a range of cell types in vitro (EFSA 2020). There is insufficient evidence to support either direct or indirect DNA damage in OTA carcinogenesis (EFSA 2020). The genotoxic power of OTA could be caused either by direct covalent binding to DNA or as a consequence of OTAinduced oxidative damage (Gupta et al 2017)
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