Unraveling Hypothalamus-Pituitary dysregulation: Hypergonadotropism in F1 progeny due to prenatal exposure to hexavalent chromium.

The endocrine disruptor hexavalent chromium [Cr(VI)] is a proven reproductive toxicant. We recently demonstrated that prenatal Cr(VI) exposure causes testicular resistance to gonadotropins, resulting in hypergonadotropic hypoandrogenism in F1 rats. However, the mechanism driving hypergonadotropism in F1 rats exposed to Cr(VI) prenatally remains an enigma. Therefore, we hypothesized that 'Prenatal Cr(VI) exposure may disrupt steroid hormones-mediated negative feedback regulation of the hypothalamic GnRH, and its receptor in the pituitary of F1 rats, leading to hypergonadotropism.' We administered potassium dichromate (50, 100, or 200 mg/L) to pregnant rats through drinking water between days 9 and 14, and their male F1 offspring were euthanized at 60 days of age. Prenatal Cr(VI) exposure in F1 rats resulted in the accumulation of Cr in the hypothalamus and pituitary. Western blot detected decreased hypothalamic GnRH, Kisspeptin1, and its receptor GPR54, along with diminished ERα, AR, aromatase, and 5α reductase, and GnRH regulatory transcription factors Pit-1 and GATA-4 proteins. Immunohistochemical studies revealed increased immunopositivity of GnRH receptor, AR, 5α reductase, ERα, ERß, and aromatase proteins in the pituitary, whereas decreased Kisspeptin1, GPR54, and inhibin ß. Our findings imply that Cr(VI) exposure during the prenatal period disrupts the hypothalamic Kisspeptin-GPR54-Pit-1/GATA4-GnRH network, boosting the pituitary GnRH receptor. We conclude that prenatal exposure to Cr(VI) alters GnRH expression in the hypothalamus and its receptor in the pituitary of F1 progeny through interfering with the negative feedback effect of androgens and estrogens.

The roles of GnRH in the human central nervous system.

It is widely known that GnRH plays a role in facilitating reproductive function via the HPG axis, and this was once believed to be its only function. However, over the last several decades important neuromodulatory roles of GnRH in multiple brain functions have been elucidated. Multiple GnRH isoforms and receptors have been detected outside the HPG-axis across different species. In this review, we focus on the human CNS where GnRH I and II isoforms and a functional GnRH I receptor have been isolated. We first describe the traditional understanding of GnRH within the hypothalamus and the pituitary and current clinical use of GnRH analogues. We then review the location and function of GnRH-producing neurons and receptors located outside the HPG axis. We next review the GnRH I and II neuron location and quantity and GnRH I receptor gene expression throughout the human brain, using the Allen Brain Map Atlas. This analysis demonstrates a wide expression of GnRH throughout the brain, including prominent expression in the basal forebrain and cerebellum. Lastly, we examine the potential role of GnRH in aging and inflammation and its therapeutic potential for neurodegenerative disease and spinal cord lesions.

Neurobiology of puberty and its disorders.

Puberty, which in humans is considered to include both gonadarche and adrenarche, is the period of becoming capable of reproducing sexually and is recognized by maturation of the gonads and development of secondary sex characteristics. Gonadarche referring to growth and maturation of the gonads is fundamental to puberty since it encompasses increased gonadal steroid secretion and initiation of gametogenesis resulting from enhanced pituitary gonadotropin secretion, triggered in turn by robust pulsatile GnRH release from the hypothalamus. This chapter reviews the development of GnRH pulsatility from before birth until the onset of puberty. In humans, GnRH pulse generation is restrained during childhood and juvenile development. This prepubertal hiatus in hypothalamic activity is considered to result from a neurobiological brake imposed upon the GnRH pulse generator resident in the infundibular nucleus. Reactivation of the GnRH pulse generator initiates pubertal development. Current understanding of the genetics and physiology of the brake will be discussed, as will hypotheses proposed to account for timing the resurgence in pulsatile GnRH and initiation of puberty. The chapter ends with a discussion of disorders associated with precocious or delayed puberty with a focus on those with etiologies attributed to aberrant GnRH neuron anatomy or function. A pediatric approach to patients with pubertal disorders is provided and contemporary treatments for both precocious and delayed puberty outlined.

Detection of the Gonadotropin Releasing Hormone (GnRH) and Its Receptor in Cancer Cell HT-1197 and HT-1376, and Effect of GnRH on Cancer Cell Cycle / 대한비뇨기과학회지

Gonadotropin releasing hormone (GnRH) is believed to be pivotal hormone in hypothalamo-pituitary gonadal axis and the hypothalamus is believed as the exclusive organ producing GnRH and pituitary is for GnRH re ceptor until recently. Some reported the exptra-hypothalamic GnRH or extra-pituitary GnRH receptors from decades ago. The aims of this study are to confirm the existence of the GnRH receptor in bladder epithelial cancer cell, HT-1197 and HT-1376, and evaluated the possible role of the GnRH on cell cycle. The GnRH and GnRH receptor were detected by immunohistochemical staining and the effect of GnRH on cell cycle change in both cell line were studied by fluorescence activated cell sorter (FACS). The control cells were cultured at media supplemented with normal serum, and experimental group were cultured at media supplemented with charcoal stripped serum (CSS) which excluding peptide hormones except exogenous GnRH with different concentration. The GnRHs and GnRH receptors were detected at both cell lines and the cell cycle analysis showed that there were little difference in proportion of cell cycle among examined 10,000 cells in both cell lines, neither control nor experimental groups. This study shows that the GnRHs and GnRH receptors exist in bladder cancer cells and GnRH did not influence on the cell cycle progression. With this study, we suppose that the bladder cancer cells produce the GnRH and GnRH receptors and the role of the GnRF produced from the bladder cancer cells might be the autocrine rather than endo-or paracrine factor.

Effects of Toluene, Xylene and Trichloroethylene on the Regulation of GnRH, GnRH Receptor and Pit-1 Gene Expression in Male Rat Hypothalamus and Pituitary / 대한산업의학회지

The workplace exposure of chemicals has steadily increased, therefore the concern for subsequent effect on reproductive outcome has been an important issue in occupational medicine. In previous studies, higher rates of spontaneous abortion, reduced fertility and menstrual disorder among women, and an impairment of sperm quantity and quality among men have been associated with a wide variety of chemical agents. This study was conducted to evaluate the effects of toluene, xylene and trichloroethylene (TCE) injection on the mRNA levels of GnRH, GnRH receptor and Pit-1 genes in male rats hypothalamus and pituitary and the effects on the plasma levels of FSH, LH, prolactin and testosterone. Sprague-Dawley male rats were divided into five groups of five each according to concentration of toluene, xylene and TCE. The rats were injected subcutaneously to 0, 50, 100, 200, 400 mg/kg body weight/day of toluene, xylene and TCE, respectively for 6 days. Rat brains were excised and hypothalamus and pituitary were separated. Reverse transcription-polymerase chain reaction (RT-PCR) and RNase protection assay (RPA) were used to evaluate the GnRH, GnRH receptor and Pit-1 mRNA levels. Plasma concentrations of FSH, LH, prolactin and testosterone were assayed by radioimulunoassay (RIA). The results were as follows; 1. GnRH, GnRH receptor and Pit-1 mRNA levels in toluene and xylene injected groups, and GnRH receptor mRNA levels in TCE injected group were lowered dose-dependently. Especially, GnRH receptor and Pit-1 mRNA levels in 200 mg/kg of toluene injected group, and GnRH, GnRH receptor and Pit-1 mRNA levels in 400 mg/kg of toluene injected group were significantly lowed than control group (p<0.05). GnRH receptor and Pit-1 mRNA levels in 400 mg/kg of xylene injected group, and GnRH receptor mRNA levels in 400 mg/kg of TCE injected group were significantly lower than control group (p<0.05). 2. The plasma levels of prolactin and testosterone in 400 mg/kg of toluene injected group, and LH in 100, 200 and 400 mg/kg of xylene injected group, and testosterone in 400 mg/kg of TCE injected group were significantly lower than control group (p<0.05). In conclusion, we speculated that toluene and xylene affected reproductive system secondarily through hypothalamus-pituitary axis, and TCE affected directly through steroidogenesis. And we recomended that further study for assessment of the reproductive toxiclty of mixed organic solvent exposures should be conducted.