A. Lafuente

Pubertal and postpubertal cadmium exposure differentially affects the hypothalamic–pituitary–testicular axis function in the rat

The effects of administration of cadmium on levels of hormones along the hypothalamic-pituitary-testicular axis were studied in rats. Male rats were treated subcutaneously from days 30 to 60 (pubertal rats) or from days 60 to 90 of life (postpubertal rats), with cadmium chloride (CdCl2) at a dose of 0.5 or 1 mg/kg, every 4 days in an alternate schedule, starting from the lower dose. Age-matched control rats received 0.3 m of saline subcutaneously every 4 days. The levels of norepinephrine (NE) increased on cadmium exposure in pubertal rats in all hypothalamic areas studied, but decreased in the median eminence. In contrast, in postpubertal rats the levels of NE only did not decrease in the posterior hypothalamus. Serotonin (5-HT) concentration in pubertal and postpubertal rats decreased in all hypothalamic regions, while serotonin turnover (measured by the ratio 5-hydroxyindolacetic acid/serotonin [5-HIAA/5-HT]) increased in the anterior hypothalamus. The serotonin metabolism was also increased in the median eminence in the pubertal and in the posterior hypothalamus in the postpubertal rats. Plasma levels of luteinizing hormone (LH) were not modified by cadmium in both age groups, but follicle stimulating hormone (FSH) levels decreased in postpubertal rats, but was not altered in pubertal rats. Plasma levels of testosterone increased in pubertal rats but decreased in postpubertal rats. Cadmium accumulation increased in the hypothalamus and testes in all the cadmium-treated animals, whereas in the pituitary accumulation of cadmium was found only in postpubertal rats. These data suggest that cadmium exerts age-dependent effects on the hypothalamic-pituitary-testicular axis function, and a disruption of the regulatory mechanisms of the hypothalamic-pituitary-gonadal axis emerges.

Cadmium effects on hypothalamic activity and pituitary hormone secretion in the male

Cadmium specifically modify amine metabolism at the central nervous system and pituitary hormone secretions. Thus, the physiological functions controlled by these hormones can be modulated by cadmium. This xenobiotic is associated with deleterious effects on the gonadal function and with changes in the secretory pattern of other pituitary hormones like prolactin, ACTH, GH or TSH. The observed changes in pituitary hormone secretion do not correlate with the modifications of central nervous system metabolism of the neurotransmitters involved in their regulation. The accumulative data indicates the existence of a disruption in the regulatory mechanisms of the hypothalamic-pituitary axis. The physiological significance of these effects remains to be elucidated.

Cadmium effects on hypothalamic-pituitary-testicular axis in male rats.

This study analyzes cadmium effects at the hypothalamic-pituitary-testicular axis. Male rats were given cadmium during puberty or adulthood. Cadmium exposure through puberty increased norepinephrine content in all hypothalamic areas studied, but not in the median eminence. Metal exposure increased serotonin turnover in median eminence and the anterior hypothalamus, while decreased it in mediobasal hypothalamus. Also, decreased plasma levels of testosterone were found. Cadmium exposure during adulthood increased norepinephrine content in posterior hypothalamus and decreased the neurotransmitter content in anterior and mediobasal hypothalamus. Decreased circulating levels of luteinizing hormone (LH) and testosterone and increased plasma follicle stimulating hormone (FSH) levels were also observed. Cadmium accumulated in all analyzed tissues. Various parameters showed age-dependent changes. These data suggest that cadmium globally effects hypothalamic-pituitary-testicular axis function by acting at the three levels analyzed and that an interaction between cadmium exposure and age emerge.

The hypothalamic-pituitary-gonadal axis is target of cadmium toxicity. An update of recent studies and potential therapeutic approaches.

This review presents an overview of neuroendocrine disruption induced by cadmium on the hypothalamic-pituitary-gonadal (HHG) axis. This review focuses on a number of hypotheses: (1) the HHG axis is a physiological target on cadmium toxicity; (2) cadmium could induce chronotoxicity on this neuroendocrine axis by disrupting the daily pattern of the HHG axis activity; (3) cadmium exposure throughout life could contribute to the oxidative stress and the circadian rhythms disruption induced by aging on the HHG; and (4) cadmium induces oxidative stress in the HHG axis so antioxidants could prevent or reduce cadmium toxicity in this system. Cadmium disrupts the regulatory mechanisms of this physiological axis, by altering neurotransmitters involved in this regulation at the hypothalamic level, altering gonadotropin hormone secretion, and by affecting testicular or ovarian structure and activity. These effects are age-dependent and they could be related to the circadian rhythms of this physiological axis. Several antioxidant agents could have a protective action against the neuroendocrine toxicity of cadmium on the reproductive system. A comprehensive view of the physiological axis may provide a better understanding about the neuroendocrine toxicity of cadmium on the reproductive system, so this perspective is recommended for undertaking further studies.

In vivo protective effect of melatonin on cadmium‐induced changes in redox balance and gene expression in rat hypothalamus and anterior pituitary

Abstract:  Cadmium (Cd) is widely used in industrial applications and is an important side contaminant of agricultural products. As an endocrine disruptor, Cd modifies pituitary hormone release. It has been shown that this metal causes oxidative stress in primary cultures of anterior pituitary cells. To examine whether Cd induces redox damage in the hypothalamic–pituitary axis in vivo and to evaluate the efficacy of the antioxidant molecule melatonin to prevent Cd activity, rats were exposed to Cd (5 p.p.m. in drinking water) with or without melatonin (3 μg/mL drinking water) for 1 month. In the anterior pituitary, Cd increased lipid peroxidation and mRNA levels for heme oxygenase‐1 (HO‐1) at both time intervals tested (09:00 and 01:00 hr, beginning of rest span and middle of activity span, respectively). Melatonin administration prevented the Cd‐induced increase in both parameters. In the hypothalamus, Cd affected the levels of mRNA for HO‐1 by decreasing it in the evening. Melatonin reduced hypothalamic HO‐1 gene expression. Cd treatment augmented gene expression of nitric oxide synthase (NOS)1 and NOS2 in the pituitary whereas melatonin decreased it, impairing the activity of Cd. Exposure to Cd increased the levels of hypothalamic NOS1 mRNA at 09:00 hr and decreased the levels of NOS2 mRNA at 01:00 hr, with melatonin treatment preventing Cd effects. Cd treatment decreased plasma thyroid‐stimulating hormone levels at both examined times, while melatonin reversed the effect of Cd at 09:00 hr and partially counteracted the effect at 01:00 hr. There were important variations between day and night in the expression of all the genes tested in both tissues. Melatonin treatment was effective reducing all examined effects of Cd, documenting its effectiveness to protect the rat hypothalamic–pituitary axis from the toxic metal effects.

Endosulfan effects on pituitary hormone and both nitrosative and oxidative stress in pubertal male rats.

The present study was undertaken to investigate in pubertal male rats possible effects of endosulfan administered throughout lactation and gestation on: (a) pituitary gene expression of prolactin, luteinizing hormone (LH), growth hormone (GH) and thyroid stimulating hormone (TSH); (b) circulating levels of these hormones; and (c) expression of nitric oxide synthase 1 and 2 (NOS1 and NOS2), and heme oxygenase-1 (HO-1) at pituitary level. Endosulfan was administered orally at the doses of 0.61 mg/kg/day or 6.12 mg/kg/day, and possible toxic effects were studied in pubertal male pups (at postnatal day 30). Gene expression was evaluated by RT-PCR and plasma hormone levels by RIA. Exposure to both administered doses down-regulated LH, GH and TSH. Treatment with 0.61 mg endosulfan/kg/day decreased prolactin expression, although its plasmatic concentration was decreased by both administered doses. LH secretion was stimulated by both doses, whereas the highest dose increased GH levels and decreased plasma TSH concentration. Endosulfan up-regulated NOS1 and NOS2. We can conclude that in pubertal male rat, prenatal and lactational exposure to endosulfan modifies expression and release of prolactin, LH, GH and TSH, and pituitary NOS1 and NOS2 mRNA levels, suggesting that nitrosative stress can be implicated in the endocrine toxicity of endosulfan at pituitary level.

Alternate cadmium exposure differentially affects amino acid metabolism within the hypothalamus, median eminence, striatum and prefrontal cortex of male rats

This work was designed to analyze the possible changes in glutamate, aspartate and glutamine content induced by cadmium exposure in the hypothalamus, striatum and prefrontal cortex of rats, using an alternate schedule of metal administration. Pubertal-adult differences were also evaluated. In adult control rats, glutamate and aspartate contents in the anterior hypothalamus decreased as compared to pubertal controls. After cadmium administration from day 30 to 60 of life, the content of anterior hypothalamic glutamate and aspartate diminished. In adult control animals, the glutamine content increased in mediobasal hypothalamus as compared to pubertal controls. After cadmium exposure from day 30 to 60 of life, the mediobasal glutamine content increased, and after cadmium treatment from day 60 to 90 of life, the mediobasal aspartate content decreased. In adult control rats the content of glutamine, glutamate and aspartate of the posterior hypothalamus decreased significantly. After cadmium administration in pubertal animals, posterior hypothalamic contents of glutamine, glutamate and aspartate diminished. Cadmium treatment of adult animals caused a decrease in glutamine content, as compared to controls. In adult control rats, only glutamate and aspartate content increased in the prefrontal cortex as compared to the values found in pubertal controls. When cadmium was administered to adult animals, only the aspartate content decreased. In the striatum, cadmium decreased the glutamine and aspartate contents when administered from day 60 to 90 of life. These data suggest that cadmium differentially affects amino acid metabolism in the hypothalamus, striatum and prefrontal cortex. Age-dependent effects of cadmium on these brain areas appeared to have occurred.

Effect of cadmium on lymphocyte subsets distribution in thymus and spleen

This work was designed to analyze the possible dose dependent effects of cadmium on the distribution of lymphocyte subsets within the thymus and spleen. Cadmium accumulation was also evaluated in these tissues. For this purpose, adult male rats were exposed for one month to 0, 5, 10, 25, 50 or 100 ppm of cadmium chloride (CdCl2) in the drinking water. In both spleen and thymus, the B lymphocytes increased with the doses of 5 and 10 ppm of CdCl2, and decreased with the doses of 25–100 ppm. In spleen, the doses of 25 and 50 ppm decreased CD4+ cells and the doses of 5 and 10 ppm increased CD8+ cells, while the percentage of thymus T, CD4+, CD8+ and CD4+-CD8+ cells was not modified by cadmium treatment at any dose used in this study. After cadmium exposure, the metal was accumulated in the spleen only from the dose of 50 ppm on, and in the thymus, from the dose of 10 ppm on. In conclusion, although the accumulation of the metal is higher in thymus than in spleen, the metal affected CD4+ and CD8+ lymphocytes at the spleen but not at the thymus.ResumenEn este trabajo se analizan los posibles efectos inducidos por la exposición al cadmio sobre las subpoblaciones linfocitarias en bazo y timo y se evalúa la acumulación del metal en estos tejidos. Para ello, se tratan ratas macho adultas durante un mes con cloruro de cadmio (CdCl2) en el agua de bebida a dosis de 0, 5, 10, 25, 50 y 100 ppm. En las ratas tratadas con 5 y 10 ppm de CdCl2, el porcentaje de linfocitos B aumenta en bazo y timo, descendiendo a partir de la dosis de 25 ppm, en ambos tejidos. En bazo de ratas expuestas a las dosis de 25 y 50 ppm, el porcentaje de linfocitos CD4+ desciende, mientras que a las dosis de 5 y 10 ppm, aumenta el porcentaje de células CD8+. Tras la exposición al cadmio, el porcentaje de linfocitos T, CD4+, CD8+ y CD4+-CD8+ no varía en el timo con ninguna de las dosis administradas en este estudio. En las ratas tratadas, el cadmio se acumula en el bazo a partir de la dosis de 50 ppm, mientras que en el timo, lo hace a partir de la dosis de 10 ppm. Estos resultados indican, por tanto, que aunque la acumulación de cadmio es mayor en timo que en bazo, este metal afecta a la proporción de linfocitos CD4+ y CD8+ en el bazo pero no en el timo.

Cadmium affects the episodic luteinizing hormone secretion in male rats: possible age-dependent effects.

Cadmium affects luteinizing hormone (LH) secretion through unknown mechanisms. The present study was undertaken to assess whether chronic exposure to low concentrations of cadmium may affect the episodic secretion of LH and if these effects are age-dependent. Male rats were given cadmium at a dose of 50 ppm in the drinking water, from day 30 to 60 or from day 60 to 90 of life. Age-matched rats with access to cadmium-free water were used as controls. At the end of the treatment, blood samples were collected every 7 min for 3 h, from 10:30 to 13.30 in conscious, freely moving rats. In control animals, mean serum LH levels and pulse duration increased with age (P < or = 0.001), and pulse frequency and the relative amplitude of LH pulses decreased (P < or = 0.001). Cadmium administration, from day 30 to 60 of life, decreased the pulse frequency and mean half-life of the hormone (P < or = 0.05, P < or = 0.01, respectively). However, no changes in any other parameters studied were observed as compared to the control group. When cadmium was administered from day 60 to 90, mean serum LH levels and the duration of LH pulses decreased (P < or = 0.05), whereas the pulse frequency increased (P < or = 0.05). The absolute and relative amplitude of the LH peaks and the mean half-life of the hormone were not changed after cadmium administration from day 60 to 90. These results indicate that low doses of cadmium change the pulsatile secretion of LH in male rats and that the effect of cadmium on episodic LH release was age-dependent.

Neurotoxic effects induced by endosulfan exposure during pregnancy and lactation in female and male rat striatum

Possible neurotoxic effects induced by endosulfan exposure during pregnancy and lactation in striatum of Sprague-Dawley female and male offspring rats have been evaluated. Dams were treated orally with 0.61 or 6.12mg of endosulfan/kg/day from the beginning of gestation until weaning. At postnatal day 60 offspring were sacrificed. We studied variations of norepinephrine, dopamine and serotonin content in striatum by High Performance Liquid Chromatography (HPLC) in these animals. Dopamine and serotonin metabolism was also determined. Endosulfan inhibits the striatal aminergic systems in adult male rats by decreasing norepinephrine and serotonin concentration and dopamine and serotonin metabolism. However, in adult female rats, only a diminution of norepinephrine content and an increase of dopamine and serotonin content were observed after endosulfan administration at the dose of 6.12mg/kg/day, whereas the concentration and the metabolism of these biogenic amines were not with the dose of 0.61mg/kg/day. Gender differences emerge in the striatal aminergic system susceptibility to endosulfan exposure during the early life stages, being the neurotoxic effects of this organochlorine insecticide higher in male than in female rats.