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Harmful algal bloom toxin microcystin-LR interferes with PP1-mediated PI3K/AKT/FOXO1 signaling in granulosa cells to disrupt ovarian follicle maturation and ovulation

ABSTRACT: Harmful algal blooms (HABs) arise from the rapid growth of algae in both marine and freshwater ecosystems due to the continuous global temperature rise and anthropogenic eutrophication. Humans are at a great risk of exposure to toxins released from HABs through drinking water, food, and recreational activities, making HAB toxins contaminants of emerging concern (CECs). The impact of HAB toxins on women’s reproductive health, however, remains poorly understood. Here, we investigated the effects of microcystin-LR (MC-LR), the most common HAB toxin, on the ovary, the female gonad, and associated ovarian functions. The results of a chronic daily oral mouse exposure model and an acute exposure using the mouse superovulation model revealed that MC-LR accumulated in the ovary and environmentally-relevant exposure to MC-LR perturbed follicle-stimulating hormone (FSH)-dependent follicle maturation to disrupt ovulation and luteinization. Using an ex vivo mouse follicle maturation and ovulation assay and in vitro culture of human primary granulosa cells, mechanistic studies such as the single-follicle RNA sequencing analysis and others elucidated that MC-LR inhibited protein phosphatase 1 (PP1) and interfered with PP1-mediated PI3K/AKT/FOXO1 signaling in granulosa cells, which suppressed follicle maturation, ovulation, luteinization, and progesterone secretion. Together, our study demonstrates that environmentally-relevant exposure to MC-LR acts a PP1 inhibitor to interfere with the PI3K/AKT/FOXO1 signaling in granulosa cells, which disrupts follicle maturation and results in adverse female reproductive outcomes. As a newly identified ovarian endocrine disrupting chemical (EDC), exposure to MC-LR poses a serious threat to women’s reproductive health and fertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE201806 | GEO | 2024/06/15

REPOSITORIES: GEO

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Project description:Microcystins (MCs) are cyclic hepatotoxins produced worldwide by various species of cyanobacteria. Their structure includes two variable amino acids (AAs) and most of the studies focused on the most toxic variant: the microcystin LR (MC-LR). However, more than 80 MC variants have been described to date. Despite ingestion being the major pathway of human exposure, few in vivo studies have demonstrated macroscopic effects on the gastro-intestinal tract, but no data are available on the affected pathways by several variants on intestinal cells. Here, using a non-selective method, we investigated for the first time the effect of MC-RR and MC-LR on the human intestinal cell line Caco-2 and compared their response at the pangenomic scale. The cells were incubated for 4 hrs or 24 hrs with the same range of sub-lethal concentrations of MC-RR or MC-LR. Low effects were observed for both variants after a short-term exposure. On the contrary, dose-dependent modulations of the genes transcription levels were noticed with MC-RR and MC-LR after 24 hrs. Furthermore, the genomic profiles induced by both variants were similar suggesting a common toxicity mechanism but with higher modulation following MC-LR than MC-RR exposure. However, the functional annotation revealed major differences between the variants effects. Indeed, the well-known MC-LR affected mainly two pathways, the oxidative stress response and the cell cycle regulation, which did not elicit significant alteration following MC-RR exposure. This work is the first comparative description of the MC-LR and MC-RR effects on a human intestinal cell model. It allowed us to suggest differences in the mechanism of toxicity for MC-RR and MC-LR. These results illustrate that the toxicity of MC variants remains a key point for risk assessment. Differentiated Caco-2 cells were exposed to microcystins in free FCS culture medium for either 4 or 24 hours. Sub-lethal concentrations of 10, 50 and 100 M-BM-5M of MC-LR or MC-RR were chosen for 4 hours, while 1, 5 and 10 M-BM-5M were selected for 24 hours. For each condition (including the controls), the solvent concentration was fixed to 2% EtOH for MC-LR and 1.5% of 80% MeOH for MC-RR. Four to five culture replicates per condition were done.

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Harmful algal bloom toxin microcystin-LR interferes with PP1-mediated PI3K/AKT/FOXO1 signaling in granulosa cells to disrupt ovarian follicle maturation and ovulation

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