Female reproductive impacts of emerging cyanobacterial harmful algal bloom toxins

Harmful algal blooms (HABs), denoted by the excessive growth or 'bloom' of cyanobacteria, have increased in frequency, duration, and intensity worldwide over the past decades, primarily due to the rise in global temperature and nutrient enrichment. The blooms of cyanobacteria release various HAB toxins, with the cyclic heptapeptide microcystin-LR (MC-LR) as the most prevalent and well-characterized. Evidence suggests that exposure to HAB toxins poses significant risks to female reproductive health. Herein, we summarized current knowledge on the female reproductive impacts of MC-LR and other HAB toxins with a focus on the ovary, oocyte, and early pregnancy events. Following ingestion, inhalation, or dermal contact, MC-LR can accumulate in the ovaries via organic anion transporting polypeptide (OATP)-mediated transport. Across mammalian, fish, and amphibian models, MC-LR has been shown to interfere with ovarian folliculogenesis, steroidogenesis, oocyte maturation, ovulation, and luteinization. Mechanistically, MC-LR inhibits protein phosphatase (PP) 1 and PP2A, triggering widespread phosphorylation dysregulation, oxidative stress, endoplasmic reticulum (ER) stress, autophagy, cytoskeletal disruption, and apoptosis in follicular cells. Beyond the ovary, exposure to MC-LR may impair fertilization, embryogenesis, decidualization, and placental health, and maternal exposure to MC-LR likely causes multi-generational toxicities. Despite increasing experimental evidence, human data remain scarce, and there are currently limited studies investigating the reproductive effects of other MC congeners and HAB toxin mixtures. Addressing these knowledge gaps is essential for assessing the female reproductive risks of exposure to HAB toxins as well as informing the development of environmental and public health policy and regulatory guidelines.