Dimethyl-Benz(a)anthracene: A mammary carcinogen and a neuroendocrine disruptor.

Polycyclic Aromatic Hydrocarbons (PAHs) are potent carcinogens. Among these, dimethylbenz(a)anthracene (DMBA) is well known for its capacity to induce mammary carcinomas in female Sprague-Dawley (SD) rats. Ovariectomy suppresses the susceptibility of this model to DMBA, thus suggesting that the inducible action of the carcinogen depends on ovarian hormones.

Short term changes in melatonin and cortisol serum levels after a single administration of estrogen to menopausal women.

Objectives: It has been well-documented that serum melatonin levels are insensitive to estrous or menstrual ovarian steroid variations in the female rat or the human. However, a negative coupling has been already demonstrated between the nocturnal serum melatonin peak and serum E2 concentration during the late premenopausal period in the woman. The objection of the present study was designed to determine if diurnal serum melatonin values can be also lowered by a single administration of estrogen.

Substance P plasma concentration during the LH preovulatory surge of the menstrual cycle in the human.

Objectives: In order to determine the exact pattern of plasma Substance P (SP) concentration during the LH preovulatory surge and the functional correlates which could exist between plasma SP, LH, 17 beta-estradiol (E2) and Progesterone, we performed a detailed analysis of changes in plasma SP concentration, during the critical phases of the LH preovulatory surge in the Human.

Methods: The experimental study was performed in 21 women between the ages of 26 and 35 years. For each subject, blood samples were taken every 15 min, between 07:00 a.

ACTH-cortisol activity during the 17beta-estradiol and LH preovulatory surges of the menstrual cycle.

Objectives: A strong positive coupling has been already documented between the adrenocortical axis and the gonadal axis at the time of the initiation of the preovulatory LH surge of the menstrual cycle in the human. The LH preovulatory surge starts in the morning at the time of the acrophase (maximal plasma cortisol values) of the cortisol circadian rhythm. Also, it was shown that morning maximal plasma cortisol values were higher during the follicular phase than during the luteal phase.

Trisomy 21: from chromosomes to mental retardation.

The first descriptions of the trisomy 21 phenotype were by Jean-Etienne-Dominique Esquirol (1838), Edouard Séguin (1846) and later by John L. H. Down in 1862.

Preventive and curative effect of melatonin on mammary carcinogenesis induced by dimethylbenz[a]anthracene in the female Sprague-Dawley rat.

Introduction: It has been well documented that the pineal hormone, melatonin, which plays a major role in the control of reproduction in mammals, also plays a role in the incidence and growth of breast and mammary cancer. The curative effect of melatonin on the growth of dimethylbenz [a]anthracene-induced (DMBA-induced) mammary adenocarcinoma (ADK) has been previously well documented in the female Sprague-Dawley rat. However, the preventive effect of melatonin in limiting the frequency of cancer initiation has not been well documented.

Long-term dysregulation of circadian and 17-beta estradiol-induced LH, prolactin and corticosterone secretion after dimethylbenz (a) anthracene administration in the Sprague-Dawley female rat.

A single intragastric administration of 7,12-dimethylbenz (a) anthracene (DMBA) has been shown, when given at 55-60 days of age, to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded by a series of neuroendocrine disturbances of the hypothalamo-pituitary-gonadal (HPG) axis, including attenuation of the preovulatory Luteinizing Hormone (LH) and Gonadotropin-Releasing Hormone (GnRH) release and amplification of the preovulatory 17beta-Estradiol (E(2)) surge. In this study, we examined the hypothesis that a single administration of DMBA could also, in the long range, induce disturbances of others neuroendocrine axis, like the Hypothalamic-Pituitary-Adrenal (HPA) axis and/or the Lactotroph axis.

Long term inhibition by estradiol or progesterone of melatonin secretion after administration of a mammary carcinogen, the dimethyl benz(a)anthracene, in Sprague-Dawley female rat; inhibitory effect of Melatonin on mammary carcinogenesis.

A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17beta-Estradiol (E2) surge. In this study, we examined the hypothesis that a single administration of DMBA increases the E2 and Progesterone inhibition of the spontaneous and Isoproterenol-induced Melatonin (MT) secretion from the pineal gland, during the latency phase.

Long-term effects of the mammary carcinogen 7,12-dimethylbenz(a) anthracene on hypothalamic gonadotropin-releasing hormone and its pituitary receptor gene expression, during the promotion stage, in female Sprague-Dawley rats.

A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of these tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory luteinizing hormone (LH) surge and amplification of the preovulatory 17beta-estradiol surge, and gonadotropin-releasing hormone (GnRH) released in vitro. In this study, we examined the hypothesis that DMBA administration decreases levels of GnRH mRNA in the preoptic area-anterior hypothalamus (POA-AH) and GnRH receptor (GnRH Rc) mRNA and protein in the anterior pituitary gland.

The influence of the route of administration of 17beta-estradiol, intravenous (pulsed) versus oral, upon DMBA-induced mammary tumour development in ovariectomised rats.

A wide variety of routes of administration and formulations are employed in estrogen replacement therapy. These exhibit differences in the pharmacokinetics and metabolism of estradiol and in the resulting biological effects. This study set out to investigate the effects of pulsed estrogen administration (via the nasal route) compared to oral therapy, as a reference, with regard to breast cancer risk.

Timing of initiation of the preovulatory luteinizing hormone surge and its relationship with the circadian cortisol rhythm in the human.

The relationship between the hypothalamo-pituitary-gonadal (HPG) axis and the hypothalamo-pituitary-adrenal (HPA) axis has been well documented in the rat. In most cases, a negative coupling was observed and an inhibitory effect of the HPA axis upon the HPG was shown. In the female rat, a marked circadian rhythm of corticosterone plasma values is observed during each day of the estrous cycle, with maximal values around 08:00 p.

Effects of the inhibition of cyclo-oxygenase 1 or 2 or 5-lipoxygenase on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1beta in the male Rat.

The limited entry of interleukin-1beta (IL-1beta) into the central nervous system has led to the hypothesis that IL-1beta acts, through IL-1beta receptors located notably on endothelial cells, on the release of prostaglandins which in turn stimulate the hypothalamic-pituitary-adrenal (HPA) axis. We used cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors, before the injection of IL-1beta, to explore the role of arachidonic acid metabolic pathways on HPA axis activation. Adult male rats were i.

Variations in plasma levels of substance P and effects of a specific substance P antagonist of the NK(1) receptor on preovulatory LH and FSH surges and progesterone secretion in the cycling cynomolgus monkey.

These studies investigated the role of substance P (SP) in the regulation of the hypothalamic-pituitary-ovarian axis in cynomolgus monkeys with normal menstrual cycles. Plasma concentrations of SP were determined in blood samples taken every morning in normally menstruating cynomolgus monkeys throughout the menstrual cycle. There was a significant decreasing linear trend of SP during the follicular phase (cycle day -13 to day 0) and a significant inverse relationship between SP plasma values and plasma 17beta-estradiol (E(2)) values from day -13 to day 0 of the adjusted cycle.

17beta-estradiol regulation of melanin-concentrating hormone and neuropeptide-E-I contents in cynomolgus monkeys: a preliminary study.

Melanin-concentrating hormone (MCH) and neuropeptide-E-I (NEI) regulate several behaviors and neuroendocrine functions in rats. Possible influence of these peptides on sexual behavior and reproduction in mammals other than rodents prompted us to investigate: 1) The sites of synthesis of MCH and NEI in the brain of a non-human primate (M. fascicularis); 2) The effect of 17 beta-estradiol (E2) benzoate (E2B) on pro-MCH-derived peptide concentrations in the hypothalamus of the ovariectomized (OVX) cynomolgus monkeys (M.

Acute intrahippocampal injection of human interleukin-1beta stimulates the anterior pituitary POMC transcription and increases plasma levels of ACTH and corticosterone in the male rat.

It has been well documented that interleukin-1beta (IL-1beta) is a major mediator for recruiting the hypothalamo-pituitary-adrenal (HPA) axis following infectious disease. The recent localization of IL-1beta receptors in neurons of the hippocampus provides further support for the role of IL-1beta as a neurotransmitter/neuromodulator in the central nervous system. In this study, we investigated whether an acute intrahippocampal injection of IL-1beta is able to rapidly stimulate HPA activity.

Ovarian steroid modulation of neurokinin contents in hypothalamus, pituitary, trigeminal nucleus, and cervical spinal cord of the ovariectomized female rat.

Ovariectomized rats were treated with estradiol benzoate (EB) and progesterone in conditions known to negatively and positively regulate gonadotropin secretion. Injection with EB decreased the plasma concentration of substance P at the time of the positive feed-back exerted by EB on gonadotropin secretion, while having no effect on the plasma concentration of neurokinin A. In the hypothalamus, EB injection enhanced the substance P and neurokinin A content, while progesterone reduced the substance P content.

Plasma substance-P and substance-K and gonadal steroids in relation to the gonadotropin surge in normal human reproductive cycles.

Purpose: This study was designed to examine changes in peripheral plasma substance-P and -K levels, their association with follicle-stimulating hormone and luteinizing hormone release in normal reproductive cycles in humans, and their correlation with plasma estradiol and progesterone.

Methods: Fourteen healthy, normally menstruating women underwent daily blood sampling (cycle day 4, 4-14 days) for measurement of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone, substances-P and -K, and daily transvaginal ultrasounds assessing follicular growth and documentation of ovulation.

Results: Estradiol peaked on day 13, luteinizing hormone and follicle-stimulating hormone peaked on day 14, and progesterone began an exponential increase on about day 13.

The in vitro effect of substance P on the GnRH-induced LH release depends on the steroidal environment and is reverted by a NK1 receptor antagonist (RP 67580) in the cycling female rat.

A previously study reported that administration of substance P on the morning of the proestrous day induces an inhibition of afternoon gonadotropin preovulatory surges in the female rat. It has also been shown, with a non-peptide specific antagonist of the neurokinin 1 (NK1) receptor (RP 67580), that this effect is mediated by NK1 receptors. The present study used perifused anterior pituitaries from proestrous morning female rats and showed that the SP modulation of the GnRH-induced LH release is markedly dependent on the steroidal environment.

Simultaneous quantitation of substance P-encoding preprotachykinin alternatively spliced mRNAs and substance P receptor NK-1 mRNA by an RNase protection assay.

Tachykinins form a family of peptides with neurotransmitter/neuromodulator function. Four tachykinins, substance P, neurokinin A, neuropeptide gamma and neuropeptide K, are encoded by the same PreProTachykinin (PPT) gene. Alternatively spliced mRNAs encode different combinations of these peptides (Brown, E.

Variations in levels of substance P-encoding beta-, gamma-preprotachykinin and substance P receptor NK-1 transcripts in the rat hypothalamus throughout the estrous cycle: a correlation between amounts of beta-preprotachykinin and NK-1 mRNA.

Using a sensitive RNase protection assay, the simultaneous quantification of hypothalamic beta-, gamma-preprotachykinin (PPT) and SP receptor NK-1 transcripts was performed throughout the estrous cycle. The amounts of these 3 transcripts were up-regulated during diestrus II-proestrus night (2-, 1.5- and 1.

Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey.

Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration.

ACTH, beta-endorphin, substance P, and corticotrophin releasing hormone in plasma and follicular fluid in hormonally stimulated menstrual cycles for in-vitro fertilization in the human.

Changes in plasma concentrations of ACTH, beta-endorphin (beta-EP) and cortisol have been found to be associated during the human menstrual cycle. Changes in hypothalamic levels of gonadotrophin releasing hormone (GnRH), beta-EP and substance P (SP) have also been associated with the oestrous cycle in the rat. Therefore, an attempt was made to measure the activity of the corticotrophic axis and SP by measuring blood and follicular fluid concentrations of ACTH, beta-EP, SP and corticotrophin releasing hormone (CRH) during the hormonal ovarian stimulation phase for in-vitro fertilization (IVF), in a series of 19 patients.

Effects of continuous infusion of interleukin 1 beta on corticotropin-releasing hormone (CRH), CRH receptors, proopiomelanocortin gene expression and secretion of corticotropin, beta-endorphin and corticosterone.

A number of recent studies suggest that interleukin 1 beta (IL-1 beta) is a major mediator of hypothalamo-pituitary-adrenal (HPA) responses following infectious aggression. We investigated whether IL-1 beta mediates long-term changes in HPA activity and studied the cellular regulation of the anterior pituitary. To mimic chronically elevated IL-1 beta production thought to occur during infectious diseases, osmotic pumps (Alzet type) were implanted in the peritoneal cavity of male rats and hIL-1 beta was infused continuously at rates of 1 or 3 micrograms/day.

CGRP in the trigeminal nucleus, spinal cord and hypothalamus: effect of gonadal steroids.

Calcitonin gene-related peptide (CGRP) contents were assayed in cervical spinal cord, trigeminal nucleus and hypothalamus throughout the estrous cycle and in male and ovariectomized rats. In the trigeminal nucleus, neither testosterone nor 17 beta-estradiol seem to affect CGRP accumulation, but progesterone seems to decrease it. In the cervical spinal cord, ovarian steroids seem to decrease CGRP while testosterone does not seem to influence it.

Substance P and neurokinin A variations throughout the rat estrous cycle; comparison with ovariectomized and male rats: II. Trigeminal nucleus and cervical spinal cord.

Substance P and neurokinin A were assayed in the trigeminal nucleus and cervical spinal cord of 4-day cycling female, ovariectomized, and male rats. During the estrous cycle, levels were largely stable in the trigeminal nucleus. In ovariectomized rats, the levels differed from those on any day of the estrous cycle suggesting a weak effect of ovarian steroids.