Prepubertal overexposure to manganese induce precocious puberty through GABAA receptor/nitric oxide pathway in immature female rats

Abstract

Gamma-aminobutyric acid (GABA) plays a critical role in regulation of gonadotropin-releasing hormone (GnRH) through GABA_A receptor (GABA_AR). Nitric oxide (NO) production has correlation with GABA and regulates GnRH secretion. This study was performed to examine the mechanisms by which manganese (Mn) accelerate puberty onset involves GABA_AR/NO pathway in the preoptic area-anterior hypothalamus (POA-AH) in immature female rats. First, female rats received daily dose of MnCl₂ 0 (saline), 2.5, 5 and 10 mg/kg b.w by oral gavage during postnatal day (PND) 21-32. Animals administered with 10 mg/kg MnCl₂ exhibited earlier puberty onset age and advanced ovary and uterus development than these in saline-treatment group. Furthermore, we found that decrease of GABA_AR result in elevated production of nitric oxide synthase1 (NOS1), NO and GnRH in the POA-AH. Second, we recorded the neuronal spikes alternation after perfusion with GABA_AR inhibitor bicuculline (BIC), GABA_AR agonist isoguvacine (isog), and MnCl₂ from the POA-AH in acute brain slices of PND21 rats. Spontaneous firing revealed a powerful GABA_AR-mediated action on immature POA-AH and confirm that MnCl₂ has a significant effect on GABA_AR. Third, we revealed that decrease in NOS1 and NO production by treatment with isog-alone or isog+MnCl₂ contribute to the decrease of GnRH in the POA-AH and a delayed puberty onset age compared to treatment with MnCl₂-alone. Together, these results suggested that excessive exposure to MnCl₂ stimulates NO production through decreased GABA_AR in the POA-AH to advance puberty onset in immature female rats.

Keywords: GABA(A)R; GnRH; Manganese; Nitric oxide; Precocious puberty.