With the acceleration of urban industrialisation around the world, industrial and domestic wastewater, which contains a large number of pollutants, is being discharged into rivers and lakes, resulting in increasingly serious eutrophication, which will lead to increased incidence of cyanobacteria blooms (1). Microcystins (MCs) are a kind of toxoid produced by freshwater cyanobacteria, including Microcystis, Aphanizomenon, Nostoc and Anabaena. Recently, with the frequent outbreaks of cyanobacteria blooms, more and more lakes are facing MC pollution (2). Amongst the over 250 known microcyanobacteria toxins, microcystin-leucine-arginine (MC-LR) has the broadest distribution and strongest toxicity. The World Health Organization limits the MC-LR concentration in drinking water to 1 µg/L (3). In China, the concentration of dissolved MC in Taihu Lake reached the highest level of 35.8 ug/L in October 2008, which greatly affected the living environment of fish and mammals (4). MC-LR can affect many organs, such as the thyroid, brain, liver, heart, intestinal tract, kidney and reproductive organs. MC-LR primarily accumulates in the liver, followed by the gonad (5).

At present, about 60,000 people suffer from food poisoning caused by cyanobacteria blooms every year (6). In China, as lake water is an important source of drinking water, its source condition directly affects the quality and safety of millions of people. Every year, a great deal of manpower, material and financial resources are spent to control cyanobacteria bloom (7). Since 2007, the cost of cleaning up Taihu Lake has exceeded 16 billion US dollars (8). Although a large amount of money has been spent on dealing with cyanobacteria blooms in Taihu Lake, the cyanobacteria bloom is still inevitable when the temperature increases every spring and summer. Compared with 2007–2018, the outbreak of cyanobacteria bloom in Taihu Lake occurred 29 days earlier in 2019 (9). Millions of people drink water from Taihu Lake, which is polluted by cyanobacteria blooms every year and may be hazardous to human organs (10).

The quality and motility of male sperms have been declining in the past 50 years, which are affected by many factors, including tobacco and alcohol use, irregular daily routine and environmental toxicants (11). Amongst them, various environmental toxins, such as dibutyl phthalate, diethylhexyl phthalate and pyrethrins, have been proved to damage male spermatozoa (12). Because these endocrine disruptors have strong estrogenic effects, they can cause great damage to the male reproductive system; moreover, they can not only damage the spermatogenesis of males exposed to these chemicals directly but also influence their male offsprings (13).

Several studies have found that MCs exhibit reproductive toxicity to male fish, mammals and frogs. After exposure to MCs for 14 days, the testis of mouse atrophied. Histological observation showed that MCs could damage the testicular structure compared with the control group (5). Further studies have shown that MC-LR can induce oxidative stress in the testis of mature rats (14). MCs can interfere with the endocrine system and induce abnormal reproductive activity in male fish, rats and frogs. Jia reported that exposure to low dosage of MC-LR damaged the reproductive system of male frogs, and oxidative damage was observed (6). Chen et al. found testicular inflammation and macrophage and lymphocyte infiltration in mouse testis after MC-LR administration (15). Another study showed that exposure to MC-LR during pregnancy or lactation can damage the reproductive function of male offspring. Compared with the control group, offspring exposed to MCs showed decreased testicular weight and disordered arrangement of spermatogenic cells with increased apoptosis rate (16).

In recent years, an increasing number of studies on mammals and fish have begun to evaluate the effects of MCs on the male reproductive system. Therefore, the purpose of this meta-analysis is to identify and evaluate the epidemiological evidence associated with exposure to MCs and damage to the male reproductive system of fish and rodents. Microcystins are highly enriched in the water environment, so fish studies are of great significance to understand the latest status of microcystins. Besides, water is necessary for human. mouse, as a kind of mammals, are closely related to human, which may suggest the reproductive damage on human.

In the past decade, environmental problems, which have attracted worldwide attention, are particularly serious in developing countries. Water bloom is one of the most serious environmental issues (1). Cyanobacteria blooms have caused the death of a large number of fishes and lead to extremely serious damage to the marine ecosystem (2). Although the Chinese government has been controlling cyanobacteria blooms in Taihu Lake for a long time, they are still rampant, which have drawn the attention of the World Health Organization (24). Although we are not directly exposed to MCs, they can enter the human body through the consumption of aquatic animals, including fish, frogs, plankton or aquatic plants, and are finally distributed in various organs of the body (25).

To our knowledge, this is the first meta-analysis that focuses on the negative effects of MC-LR on the male reproductive system. In total, nine individual meta-analyses in our systematic review were undertaken to calculate the pooled SMD of MC exposure. Amongst them, seven meta-analyses reached statistical significance (P < 0.05), and four meta-analyses showed significant positive associations. According to the data of rodent studies, sperm count (SMD = -1.7426 (95% CI: -2.2098 to -1.2754)), sperm motility (SMD = -2.8822 (95% CI: -3.9811 to -1.7834)) abnormal sperm rate (SMD = 1.6714 (95% CI: 0.9702 to 2.3726)) and serum FSH (SMD = 0.4707 (95% CI: 0.0659 to 0.8756)) demonstrated significant positive associations. According to the data of fish studies, significant positive associations were found in serum testosterone (SMD = 0.5521 (95% CI: 0.1652; 0.9391)) and serum estradiol (SMD = 0.6398 (95% CI: 0.1896 to 1.0900)). In the two remaining meta-analyses, although no significant correlation was found, serum testosterone and serum LH were still affected by MCs.

Jia et al. found a large amount of MC-LR accumulation in the testes of Rana nigromaculata by immunofluorescence staining. They found that the down-regulation of Hsd17b3 gene expression led to the inhibition of T synthesis, and that the up-regulation of CYP19A1 gene expression directly stimulated the transformation of testosterone to estradiol (7). In another study, the endocrine function of the male rana nigromaculata was affected after exposure to 1 µg/LMC in fresh water (16). MCs can affect the neurological function, sperm count, sperm motility, sperm viability, sperm progressive motility and sperm viability of rats. Histological examination showed that the testis atrophied and the structure of seminiferous tubules was damaged in the MC group (18). The main function of Leydig cells is to produce androgen, which is necessary for spermatogenesis, maturation and the maintenance of libido (20). A decrease in testosterone may reflect damage of interstitial cells caused by MC-LR exposure. As noted above, MCs likely pass through the blood–testis barrier and affect the spermatogenesis of the testis and the production of testosterone, resulting in the weakening of libido in male rats.

At present, the mechanism by which MC-LR affects the male reproductive system is unclear. Fish studies have found that MC-LR may delay gonadal maturation by interfering with the growth hormone/insulin-like growth factor system. Moreover, the gonadal development of males was found to be more easily affected by MC-LR than that of females (26). However, Qin Qiao et al. found that female zebrafish are more vulnerable to MC-LR exposure than males (27). In mouse studies, MC-LR can induce immune response of Sertoli cells, germ cells and interstitial cells by activating phosphatidylinositol 3-kinase/AKT/nuclear factor kappa B, thus producing proinflammatory cytokines and chemokines and damaging the function of the main testicular cells, which is crucial to the spermatogenic function and testosterone level of the testis (5).

This study has several limitations. The relationship between MC exposure and male reproductive system damage was affected by many factors, which may be the cause of heterogeneity, and the exposure time and dose may be the source of heterogeneity. In most teleost fish, the dominant male hormone should be 11-keto-testosterone (28). In addition, 11-keto-testosterone is found in higher levels in the plasma of males than in females, whereas this is usually not the case for testosterone (29). 11-keto-testosterone is generally more effective than testosterone in stimulating secondary sexual characters, reproductive behavior and spermatogenesis (30). However, studies that are involved in the meta-analysis did not explore the 11-keto-testosterone concentration of fishes with MCs exposure. We hope researches could focused more on the role of 11-keto-testosterone when exploring the damage on fish reproductive system. Despite these limitations, our findings have practical implications. We evaluated the effects of MC exposure on the reproductive system of mouse and fish. In addition, we conducted several subgroup analyses to explore the effects of several key factors on the study. Furthermore, the dose–response relationship curve can be used to intuitively observe the relationship between short-term and long-term exposure, as well as between low-dose and high-dose exposure.

The evidence provided by this meta-analysis suggested that exposure to MC-LR affects the male reproductive system, including the sperm, testis and testosterone. Moreover, the exposure time and dose affect the relationship between MC-LR exposure and parameters related to the male reproductive system. Further research should focus on the effects of long-term low-dose exposure and the effects of MC-LR on humans. In addition, it is also necessary to further explore the mechanism of MC-LR toxic effect on the male reproductive system.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

SL: Conceptualization, Methodology, Investigation, Writing - original draft preparation. BH: Data curation, Formal analysis, Writing - review and editing. HL: Supervision, Resources, Writing - review and editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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