Exposure to Cadmium Alters the Population of Glial Cell Types and Disrupts the Regulatory Mechanisms of the HPG Axis in Prepubertal Female Rats.

Despite the fact that the brain is susceptible to neurotoxicity induced by cadmium (Cd), the effects of Cd on the neuroanatomical development in the hypothalamus and regulatory mechanisms of the hypothalamic-pituitary-gonadal (HPG) axis are not fully understood. To clarify this issue, we investigated the effects of 25 mg/kg BW/day cadmium chloride (CdCl2) on neuroanatomical alterations in the hypothalamus of prepubertal female rats. Twenty-four Sprague-Dawley rats were randomly assigned to two groups (n = 12), and CdCl2 was administered via gavage from postnatal days (PND) 21 to PND35. The results of the stereological analysis demonstrated that prepubertal exposure to Cd reduced the number of neurons and oligodendrocytes in the arcuate (ARC) and dorsomedial hypothalamus nucleus (DMH) nuclei. In contrast, Cd exposure increased the number of microglial cells in the ARC and DMH nuclei. Cd exposure decreased the mRNA levels of gonadotropin-releasing hormone (GnRH) and increased the mRNA levels of RFamide-related peptide (RFRP-3), but not kisspeptin (Kiss1) in the hypothalamus. Moreover, hormonal assay showed that Cd exposure caused a reduction in the concentration of gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum. Immunohistochemical expression of RFRP-3 in neuronal cell bodies demonstrated that the mean number of RFRP-3 expressing neurons in the DMH nucleus of cadmium-treated rats was dramatically higher than the vehicle group. Overall, exposure to Cd during the prepubertal period alters the population of neurons and glial cell types in the hypothalamus. Additionally, Cd exposure disrupts the regulatory mechanisms of the HPG axis.

Impaired follicular development and endocrine disorders in female rats by prepubertal exposure to toxic doses of cadmium.

Cadmium (Cd) has been associated with several physiological problems including reproductive and endocrine system dysfunction resulting in temporary infertility. The principal objective of this project was to investigate the effects of prepubertal exposure to toxic doses of Cd on puberty onset, the endocrine system, and follicular development. For this purpose, 16 female Sprague-Dawley rats weaned on postnatal day (PND) 21 were randomly divided into 4 groups (n = 4 per group). The treatments were as follows: 0, 25, 50, and 75 mg/kg/day of cadmium chloride (CdCl2) by oral gavage from PND 21 to observation of first vaginal opening (VO). The results demonstrated that prepubertal exposure to different doses of CdCl2 delays the age of VO, first diestrus, and first proestrus via altering the concentrations of estradiol and progesterone. The low level of these steroid hormones contributed to lower differentiation and maturation of follicles and it finally led to reduced ovarian reservoir of follicles and impaired follicular development. The number of atretic follicles and secondary follicles with premature cavity increased in rats that received a high dose of CdCl2, whereas the number of secondary follicles and corpora luteum decreased in the same circumstances. Taken together, these data suggest that prepubertal exposure to toxic doses of Cd delays the onset of puberty via disorderliness in the concentration of steroid hormones and reduces the ovarian reservoir of follicles, as well as folliculogenesis.

Expression of melanocortin-4 receptor and agouti-related peptide mRNAs in arcuate nucleus during long term malnutrition of female ovariectomized rats.

OBJECTIVE: Melanocortin-4 receptor (MC4R) and agouti-related peptide (AgRP) are involved in energy homeostasis in the rat. The aim of the present study was to evaluate the expression of MC4R and AgRP mRNAs in arcuate nucleus (ARC) during long term malnutrition of female ovariectomized rats. MATERIALS AND METHODS: Ten female ovariectomized rats were divided into two equal groups (n=6) of normal and restricted diet groups. Using real-time PCR, the relative expressions (compared to controls) of MC4R and AgRP mRNAs were compared between both diet groups. RESULTS: The relative expression of MC4R and AgRP mRNA in the ARC of female ovariectomized rats during long term malnutrition was higher than those with normal diet (P<0.05). CONCLUSION: Changes in the relative expression level of MC4R and AgRP mRNAs during long term malnutrition of rat indicated a stimulatory role of MC4R and AgRP in regulating energy balance in ARC of rat hypothalamus.

Increased litter size and suckling intensity inhibit KiSS-1 mRNA expression in rat arcuate nucleus.

OBJECTIVES: The effect of litter size and suckling intensity on the expression of KiSS-1 mRNA in the arcuate nucleus (ARC) of rats were evaluated. MATERIALS AND METHODS: Thirty two pregnant and four non-lactating ovariectomized (as control group) rats were used in this experiment. Lactating rats were allotted to eight equal groups. In three groups, litter size was adjusted to 5, 10, or 15 pups upon parturition and allowed to suckle their pups continuously by 8 days postpartum. In the other three groups, litter size was adjusted to five upon birth; the pups were separated from the dams for 6 hr on day 8 postpartum, after which the pups were allowed to suckle their dams for 2.5, 5, or 7.5 min prior to killing the dams. Two groups of lactating rats with either 10 or 15 pups were separated from their pups for 6 hr on day 8 postpartum, after which the pups were allowed to suckle their dams for 5 min before the dams were killed on day 8 postpartum. The ARC was removed and the expression of KiSS-1 mRNA was evaluated, using real-time PCR. RESULTS: The expression of KiSS-1 mRNA in the ARC was decreased as the litter size and intensity of suckling stimulus were increased. The effect of suckling intensity on the expression of KiSS-1 mRNA was more pronounced than that of litter size. CONCLUSION: Increased litter size and suckling intensity decreased KiSS-1 mRNA expression in the ARC which may contribute to lactation anestrus in rat.