Effect of Cyanotoxins on the Hypothalamic–Pituitary–Gonadal Axis in Male Adult Mouse

Abstract

BackgroundMicrocystins LR (MC-LR) are hepatotoxic cyanotoxins that have been shown to induce reproductive toxicity, and Hypothalamic–Pituitary–Gonadal Axis (HPG) is responsible for the control of reproductive functions. However, few studies have been performed to evaluate the effects of MC-LR on HPG axis. This study aimed to investigate the MC-LR-induced toxicity in the reproductive system of mouse and focus on the HPG axis.MethodsAdult male C57BL/6 mice were exposed to various concentrations of MC-LR (0, 3.75, 7.50, 15.00 and 30.00 µg/kg body weight per day) for 1 to 14 days, and it was found that exposure to different concentrations of MC-LR significantly disturbed sperm production in the mice testes in a dose- and time-dependent manner. To elucidate the associated possible mechanisms, the serum levels of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assessed. Meanwhile, PCR assays were employed to detect alterations in a series of genes involved in HPG axis, such as FSH, LH, gonadotropin-releasing hormone (GnRH) and their complement receptors. Furthermore, the effect of MC-LR on the viability and testosterone production of Leydig cells were tested in vitro. Results: MC-LR significantly impaired the spermatogenesis of mice possibly through the direct or indirect inhibition of GnRH synthesis at the hypothalamic level, which resulted in reduction of serum levels of LH that lead to suppression of testosterone production in the testis of mice.ConclusionsMC-LR may be a GnRH toxin that would disrupt the reproductive system of mice.

A review of reproductive toxicity of microcystins

“…MC-LR exposure led to an initial increase and subsequent decrease in the expressions of Fsh␤, Lh␤, and the secretion of FSH, LH, and testosterone. Similarly, Xiong et al [67] also demonstrated that MC-LR impaired spermatogenesis possibly through the direct or indirect inhibition of GnRH synthesis at the hypothalamic level in C57BL/6 mice.…”

“…These results showed that oxidative stress was responsible for apoptosis induced by MC-LR, and the reduced production of testosterone in Leydig cells could result in reproductive toxicity [62]. However, two studies later by the same group [51,66] and a further study [67] reported that MC-LR did not enter and had no cytotoxicity on Leydig cells. Because MC-LR was not observed to be distributed to Leydig cells in vitro, the authors inferred that in the acute/subacute experiment, MC-LR did not directly act on the testosterone synthesis pathway in Leydig cells.…”

“…The authors inferred that the changes of serum hormone levels induced by MC-LR may be combined effects of liver damage and hypothalamic-pituitary system damage, but not a direct effect on testis [66]. Similarly, Xiong et al [67] also demonstrated that MC-LR impaired spermatogenesis possibly through the direct or indirect inhibition of GnRH synthesis at the hypothalamic level. However, in female mice exposed to MCs [52], serum progesterone was decreased, but there was no significant difference in FSH, LH, or estradiol serum levels compared to control animals.…”

“…A possible explanation is cell membrane damage in Li et al's experiment [62,66]. Thus, the toxicity of MC-LR on Leydig cells and testosterone synthesis could be achieved in an indirect way, with a large probability that the dysfunction of Leydig cells is a secondary effect due to the damage of the hypothalamic-pituitary-gonad (HPG) axis caused by MC-LR [51,66,67]. The underlying mechanisms need further research.…”

<p>Some of the Factors Involved in Male Infertility: A Prospective Review</p>

“…Any abnormality in the system can lead to infertility. [88][89][90] If the brain is unable to produce gonadotropic releasing hormone (GnRH), this disorder results in a lack of testosterone and stopping sperm production. 91,92 Lack of GnRH causes a group of disorders known as hypogonadotropic hypogonadism.…”