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Title: Toxicological effects of individual and mixtures of mycotoxins and persistent organochloride pesticides on reproduction using in vitro bioassays
Author: Eze, Ukpai Agwu
ISNI:       0000 0004 7660 7597
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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There is a gradual decline in human reproductive health globally and environmental and food-borne toxins, including mycotoxins and persistent organochloride pesticides (POPs) have been suggested as one of the possible causes. However, the reproductive health effects of both individual and mixtures of these toxins are still poorly characterised. The application of suitable in vitro cellular models and relavant bioassays are critical to the understanding of these effects. The MMV-Luc, MA-10 Leydig and BeWo placental cell lines were used to evaluate the effects of individual and mixtures of selected mycotoxins and POPs on reproduction. In the reporter gene assay (RGA), zearalenone (ZEN) and α-zearalenol (α-ZOL) at biologically relevant concentrations induced oestrogen receptor (ER) transcriptional response (75% - 85%) relative to the response mediated by 10 nM of 17β-oestradiol (E2) standard arbitrarily set at 100% response. Co-exposure of single mycotoxins with clinically relevant concentrations of E2 (0.05 nM or 10 nM) had stimulatory or inhibitory effect on E2-mediated ER transcriptional response depending on dose whereas mixtures of equimolar concentration (50 µM) of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDT) and 1, 1, 1-trichloro-2,2-bis (p-chlorophenyl)-ethane (p,p'-DDE) with E2 at similar doses completely abolished ER response. Among single toxins, deoxynivalenol (DON) and ochratoxin A (OTA) were significantly cytotoxic to both MA-10 and BeWo cell lines. In the endocrine function, ZEN and its metabolites elevated progesterone (P4) production, but inhibited testosterone level in MA-10 cells whereas they had no effect on P4 levels in BeWo cells, but significantly increased E2 production. All the tested mycotoxins and POPs significantly inhibited the production of beta-human chorionic gonadotropin (β-hCG) in BeWo placental cells. The effects of binary mycotoxin and POPs combinations on cell viability and hormone production showed synergistic, additive or antagonistic effects depending on the cell model, tested concentrations or mixture. In the quantitative real-time PCR (RT-qPCR) assay, ZEN, p,p'-DDT, and their combination significantly elevated the mRNA expression of genes of the insulin-like growth factor (IGF) axis (IGF2BP1 and IGF2R), imprinted genes (PHLDA2 and MEG3) and genes for DNA methylation (MTHFR and MDB2) in BeWo cells. Overall, this study provides the first comprehensive evidence that exposure to mycotoxins and/or POPs, individually or in combination, could have adverse effects on reproduction and development through multiple mechanisms.
Supervisor: Gong, Yun Yun ; Huntriss, John ; Routledge, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available