Unpredictable Chronic Stress-Induced Reproductive Suppression Associated with the Decrease of Kisspeptin Immunoreactivity in Male Mice

Abstract

Environmental stress affects various parts of mammals typically through the circulation of stress hormones. It has been identified as one of the possible reasons for male reproductive difficulties, but the complex mechanisms responsible for stress-induced reproductive suppression are poorly understood. Here, we examined the relationship between chronic environmental stress and hypothalamic kisspeptin, a recently discovered upstream regulator of the reproductive endocrine feedback system. We studied male mice under an unpredictable chronic stress procedure to replicate the situation of animals under chronic stress. Histological and immunohistochemical analyses were performed focusing on kisspeptin neurons in the arcuate hypothalamic nucleus (ARC) and DNA fragmented cells in seminiferous tubules. Although the ARC was not morphologically altered in either the stressed or non-stressed group, granular kisspeptin immunoreactivities decreased slightly in the stress group. In the testes of the stress group, several signs of testicular degeneration were observed, including increased numbers of ssDNA-positive cells per seminiferous tubule, thinning, vacuoled seminiferous epithelia and multinucleated giant cells. The decreases in kisspeptin in the stress group might be due to other hypothalamic peptides, such as corticotropin-releasing hormone and leptin, whose receptors are known to coexpress in the ARC. In addition, environmental stress directly and indirectly affects testicular function through stress hormones and gonadotropins. In summary, our findings enhance the understanding of stress-induced reproductive suppression possibly mediated by kisspeptin in the ARC.

The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders

“…In agreement with the findings of our aforementioned study, the administration of LPS decreased hypothalamic Kiss1 mRNA expression and kisspeptin immunoreactivity, and the co-administration of kisspeptin partially restored serum LH levels in female rats [76]. In addition, other kinds of stress, such as psychosocial, unpredictable chronic (six randomly assigned stressors), and hypoglycemic stress, also reduced hypothalamic Kiss1 mRNA expression and kisspeptin neuron activity [77][78][79]. Some studies have also evaluated the intermediate factors that transfer stress signals to kisspeptin neurons.…”

“…As a result, it was found that both the central administration of CRH and the peripheral administration of corticosterone reduced hypothalamic Kiss1 mRNA expression and kisspeptin neuron activity in female rats and mice, indicating that activation of the HPA axis is involved in the stressinduced suppression of the kisspeptin system [77,80]. Interestingly, relatively severe stress protocols were used in these studies; i.e., high-dose LPS (1-5 mg/kg) or repeated LPS administration protocols (three consecutive injections at 24-h intervals), to evaluate the effects of immune stress [75,76,81,82], and chronic (once per day for four weeks) or combined (restraint and isolation) protocols were used to evaluate the effects of unpredictable and psychosocial stress [78,79]. Similarly, we found that a subseptic dose (500 μg/kg) of LPS did not affect hypothalamic Kiss1 mRNA expression in female rats, indicating that only chronic or severe stress affects the kisspeptin system [81,82].…”

The combined effect of clothianidin and environmental stress on the behavioral and reproductive function in male mice

“…All gels were weighed daily to estimate the amounts of the putative CTD exposure. In the four stress groups, the mice were subjected to an unpredictable chronic stress procedure as described in our earlier report [ 14 ] with some modifications. Briefly, the following six stressors were used: 5 min forced swimming in water at room temperature (RT), 24 hr food and water deprivation, continuous overnight illumination, 30 min horizontal cage shaking (80 rpm), 24 hr switching of cagemates (being housed with another mouse) and 24 hr wet bedding.…”

HSP70 overexpression may play a protective role in the mouse embryos stimulated by CUMS

“…After administration of PMSG/hCG to induce superovulation, we found that moderate or severe stress mice stimulated by CUMS had a decreased ovarian response and oocyte development potential. Tetsushi HIRANO et al also reported a reproductive suppression male mice model induced by CUMS [ 30 ]. This negative outcome resulted from multilevel interactions among the hypothalamic-pituitary- adrenal axis and the hypothalamic-pituitary-gonadal axis, the immune system, and the autonomic nervous system.…”