In vivo effects of cadmium on signaling and secretion of pituitary gonadotrophs in male mice are time-dependent

Cadmium is a heavy metal found widely in the environment, originating from industrial emissions, mining activities, phosphate fertilizers, and cigarette smoke. It is an endocrine-disrupting chemical that mimics essential metals such as calcium and zinc, interfering with hormone signaling. Due to its long biological half-life, cadmium bioaccumulates in organisms, raising concerns about its long-term effects on endocrine and reproductive health. Cadmium's reproductive toxicity is well documented, with studies highlighting its impact on gonadotropin regulation and testicular function. However, its specific effects on calcium (Ca2+) signaling in gonadotrophs remain poorly understood. This study aims to determine whether cadmium disrupts Ca2+-dependent signaling mechanisms essential for gonadotropin secretion. To address this, we used an adult male mouse model to assess pituitary cadmium accumulation, gonadotroph responsiveness to GnRH, and alterations in Ca2+ mobilization patterns. Our results show that cadmium exposure leads to pituitary bioaccumulation, prolonged endocrine disruption, and gonadotroph hyperplasia. Initially, gonadotroph responsiveness to GnRH declines, but over time, altered Ca2+ oscillation patterns and increased gonadotropin secretion emerge. A transition from normal oscillatory Ca2+ signaling to biphasic responses was observed, along with sustained phospholipase C-β (PLCβ) activation, suggesting persistent intracellular signaling disruptions. In addition, cadmium exposure resulted in testicular atrophy, increased apoptosis, and reduced sperm count. Testosterone levels declined, while the gonadotroph population increased, highlighting an imbalance in endocrine regulation. These findings suggest that cadmium induces reproductive toxicity through a combination of direct testicular damage and disruption of gonadotroph calcium signaling and hormone secretion, leading to testicular dysfunction that is relevant to public health.