Neonatal exposure to zearalenone induces long term modulation of ABC transporter expression in testis

The BCRP (ABCG2) transporter is responsible for the efflux of chemicals from the placenta to the maternal circulation. Inhibition of BCRP activity could enhance exposure of offspring to environmental chemicals leading to altered reproductive, endocrine, and metabolic development. The purpose of this study was to characterize environmental chemicals as potential substrates and inhibitors of the human placental BCRP transporter. The interaction of BCRP with a panel of environmental chemicals was assessed using the ATPase and inverted plasma membrane vesicle assays as well as a cell-based fluorescent substrate competition assay. Human HEK cells transfected with wild-type BCRP or the Q141K genetic variant, as well as BeWo placental cells that endogenously express BCRP were used to further test inhibitor and substrate interactions. To varying degrees, the eleven chemicals inhibited BCRP activity in activated ATPase membranes and inverted membrane vesicles. Further, genistein, zearalenone, and tributyltin increased the retention of the fluorescent BCRP substrate, Hoechst 33342, between 50–100% in BeWo cells. Additional experiments characterized the mycotoxin and environmental estrogen, zearalenone, as a novel substrate and inhibitor of BCRP in WT-BCRP and BeWo cells. Interestingly, the BCRP genetic variant Q141K exhibited reduced efflux of zearalenone compared to the wild-type protein. Taken together, screening assays and direct quantification experiments identified zearalenone as a novel human BCRP substrate. Additional in vivo studies are needed to directly determine whether placental BCRP prevents fetal exposure to zearalenone.

show abstract

“…45 Interestingly, zearalenone exposure to rats, albeit postnatally, decreases expression of Bcrp mRNA and protein in the testes. 46 …”

Section: Discussionmentioning

confidence: 99%

In vitro screening of environmental chemicals identifies zearalenone as a novel substrate of the placental BCRP/ABCG2 transporter

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Zearalenone (ZEA), produced by several Fusarium species, can exert estrogen-like activity and cause reproductive dysfunction due to its chemical structure [ 1 , 2 ]. ZEA can perturb the differentiation of cells, reduce the generation of reproductive cells and induce the death of germ cells [ 3 , 4 ]. Human and animal exposure to ZEA may be attributed to the consumption of cereal grains that have been contaminated by toxigenic molds that may produce mycotoxins and their metabolites.…”

Section: Introductionmentioning

confidence: 99%

ROS-Mediated Cell Cycle Arrest and Apoptosis Induced by Zearalenone in Mouse Sertoli Cells via ER Stress and the ATP/AMPK Pathway

Zheng

Wang

et al. 2018

Toxins

View full text Add to dashboard Cite

Zearalenone (ZEA) can perturb the differentiation of cells, reduce the generation of reproductive cells and induce a death of germ cells, but the molecular mechanism remains unclear. In order to investigate the potential mechanism of ZEA-induced cell cycle arrest and apoptosis, we studied the effects of ZEA on cell proliferation, cell-cycle distribution, cell-cycle-related proteins, cell death, cell apoptosis, ROS generation and the ATP/AMPK pathway in Sertoli cells. The role of ROS, ER stress and the ATP/AMPK pathway in ZEA-induced cell-cycle arrest and cell apoptosis was explored by using the antioxidant NAC, ER stress inhibitor 4-PBA and the AMPK inhibitor dorsomorphin, respectively. The results revealed that ZEA inhibited the cell proliferation, influenced the distribution of the cell cycle and induced cell apoptosis through the ATP/AMPK pathway. The ATP/AMPK pathway was regulated by ER stress that was induced by ROS generation after exposure to ZEA. Taking these together, this study provided evidence that ROS regulated the process of ZEA-induced cell cycle arrest and cell apoptosis through ER stress and the ATP/AMPK signal ways.Keywords: Zearalenone; cell cycle; cell apoptosis; ROS; ER stress; AMPK signaling; Sertoli cells Key Contribution: Zearalenone induced the cell cycle arrest and apoptosis through ROS-ER stress-AMPK pathway in mouse sertoli cells.

show abstract

“…It is well known that both in females and males, the regulation of estrogen signaling is important in maintaining the normal functionality of reproductive systems [ 4 – 6 ]. Due to their characteristics as highly active nonsteroidal estrogens with hormonal activity, ZEA and its reduced metabolites (such as β-zearalenol) can evidently disrupt the endocrine balance in either females or in males [ 7 – 9 ]. In livestock production, especially in pig production [ 2 – 4 ], both low and high concentrations of ZEA are shown to have adverse effects, leading to hyperestrogenic syndrome, abortion and reproductive failure [ 10 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Induced by Zearalenone in Porcine Granulosa Cells and Its Rescue by Curcumin In Vitro

et al. 2015

View full text Add to dashboard Cite

Oxidative stress (OS), as a signal of aberrant intracellular mechanisms, plays key roles in maintaining homeostasis for organisms. The occurrence of OS due to the disorder of normal cellular redox balance indicates the overproduction of reactive oxygen species (ROS) and/or deficiency of antioxidants. Once the balance is broken down, repression of oxidative stress is one of the most effective ways to alleviate it. Ongoing studies provide remarkable evidence that oxidative stress is involved in reproductive toxicity induced by various stimuli, such as environmental toxicants and food toxicity. Zearalenone (ZEA), as a toxic compound existing in contaminated food products, is found to induce mycotoxicosis that has a significant impact on the reproduction of domestic animals, especially pigs. However, there is no information about how ROS and oxidative stress is involved in the influence of ZEA on porcine granulosa cells, or whether the stress can be rescued by curcumin. In this study, ZEA-induced effect on porcine granulosa cells was investigated at low concentrations (15 μM, 30 μM and 60 μM). In vitro ROS levels, the mRNA level and activity of superoxide dismutase, glutathione peroxidase and catalase were obtained. The results showed that in comparison with negative control, ZEA increased oxidative stress with higher ROS levels, reduced the expression and activity of antioxidative enzymes, increased the intensity of fluorogenic probes 2’, 7’-Dichlorodihydrofluorescin diacetate and dihydroethidium in flow cytometry assay and fluorescence microscopy. Meanwhile, the activity of glutathione (GSH) did not change obviously following 60 μM ZEA treatment. Furthermore, the underlying protective mechanisms of curcumin on the ZEA-treated porcine granulosa cells were investigated. The data revealed that curcumin pre-treatment significantly suppressed ZEA-induced oxidative stress. Collectively, porcine granulosa cells were sensitive to ZEA, which may induce oxidative stress. The findings from this study clearly demonstrate that curcumin is effective to reduce the dysregulation of cellular redox balance on porcine granulosa cells in vitro and should be further investigated for its protective role against ZEA in animals.

show abstract

Neonatal exposure to zearalenone induces long term modulation of ABC transporter expression in testis

Cited by 31 publications

References 48 publications

In vitro screening of environmental chemicals identifies zearalenone as a novel substrate of the placental BCRP/ABCG2 transporter

In vitro screening of environmental chemicals identifies zearalenone as a novel substrate of the placental BCRP/ABCG2 transporter

ROS-Mediated Cell Cycle Arrest and Apoptosis Induced by Zearalenone in Mouse Sertoli Cells via ER Stress and the ATP/AMPK Pathway

Oxidative Stress Induced by Zearalenone in Porcine Granulosa Cells and Its Rescue by Curcumin In Vitro

Contact Info

Product

Resources

About