Use of a novel ovary-on-a-chip to screen for female reproductive toxicity of microcystins

Shuo Xiao1, Jingshan Xu1, Yingzheng Wang1, Bryan Brooks2, Saurabh Chatterjee1 and Geoffrey Scott1, (1)University of South Carolina, Department of Environmental Health Sciences, NIEHS Center for Oceans and Human Health and Climate Change Interactions, Columbia, SC, United States, (2)Baylor University, Environmental Science, Center for Reservoir and Aquatic Systems Research, Institute of Biomedical Studies, Baylor University, Waco, TX, United States
Abstract:
Harmful algal bloom (HAB) cyanotoxins have been reported to exhibit neurotoxicity, hepatotoxicity, and endocrine disruption. However, effects of HAB toxins on women’s reproductive health has been scarcely investigated. The ovary is the primary female reproductive organ and contains various developmental stages of follicles as the functional unit. We have recently developed an ovary-on-a-chip by culturing individual follicles using the alginate hydrogel encapsulation method and microfluidic technology. The ovary-on-a-chip maintains the 3D architecture of follicles and recapitulates follicle development, hormone secretion, oocyte maturation, and ovulation in vivo. Here, we used the ovary-on-a-chip to screen for the ovarian toxicity (ovotoxicity) of 6 microcystins (MC), including MC-LA, LF, LR, LY, RR, and YR. Secondary follicles were isolated from 16-day old CD-1 female mice and cultured using the ovary-on-a-chip for 8 days. Follicles were treated with 0, 0.1, 1, and 10 μM (equivalent to 0-104 ppb) different MCs from day 0 to 8, and the follicle survival rate, development, hormone secretion, and ovulation were evaluated. Results indicated that MC-LF was the most ovotoxic MC with 100% of follicles dead in the 1 and 10μM treatment groups on day 8, and MC-RR was the least ovotoxic MC with 100% of follicles survived in all treatment groups on day 8. The MC-LF at 0.1μM and MC-LY at 0.1 and 1μM did not change follicle survival and development, but significantly decreased the secretion of 17b-estradiol, suggesting the endocrine disrupting effect. MC-LR, the most well-characterized MC, did not significantly decrease follicle survival rate in all treatment groups. However, follicles treated with 10μM MC-LR had significantly increased androgen production and >50% follicles had abnormal ovulation on day 8. In summary, our results suggest that MC variants exhibit differential ovotoxicties and exposure to MCs may increase risks of female premature ovarian failure, hormonal imbalance, anovulation, and sub- or infertility.
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