Environmental control of biological rhythms: effects on development, fertility and metabolism.

Internal temporal organisation properly synchronised to the environment is crucial for health maintenance. This organisation is provided at the cellular level by the molecular clock, a macromolecular transcription-based oscillator formed by the clock and the clock-controlled genes that is present in both central and peripheral tissues. In mammals, melanopsin in light-sensitive retinal ganglion cells plays a considerable role in the synchronisation of the circadian timing system to the daily light/dark cycle. Melatonin, a hormone synthesised in the pineal gland exclusively at night and an output of the central clock, has a fundamental role in regulating/timing several physiological functions, including glucose homeostasis, insulin secretion and energy metabolism. As such, metabolism is severely impaired after a reduction in melatonin production. Furthermore, light pollution during the night and shift work schedules can abrogate melatonin synthesis and impair homeostasis. Chronodisruption during pregnancy has deleterious effects on the health of progeny, including metabolic, cardiovascular and cognitive dysfunction. Developmental programming by steroids or steroid-mimetic compounds also produces internal circadian disorganisation that may be a significant factor in the aetiology of fertility disorders such as polycystic ovary syndrome. Thus, both early and late in life, pernicious alterations of the endogenous temporal order by environmental factors can disrupt the homeostatic function of the circadian timing system, leading to pathophysiology and/or disease.

Autocrine regulation of prolactin secretion by endothelins: a permissive role for estradiol.

We have previously found that lactotrophs express and secrete endothelin-like peptides that influence prolactin (PRL) secretion in an autocrine fashion. We have also observed that the incidence of endothelin-immunoreactive lactotrophs is markedly affected by ovarian steroids. In this study, we examined how the ovarian steroid background determines the efficiency of the endothelin-mediated autocrine feedback regulation of PRL secretion. Ovariectomized adult female rats were used throughout these studies. Steroid replacements were made by sc implantation of Silastic capsules immediately following ovariectomy. Eight to 10 wk later, three animals from each treatment group (no steroid control, estradiol, progesterone, estradiol plus progesterone) were sacrificed by decapitation, and the anterior pituitary cells were enzymatically dispersed using collagenase and hyaluronidase. A PRL-specific reverse hemolytic plaque assay was used to measure PRL secretion at the single-cell level. BQ123, a synthetic cyclic pentapeptide with distinctive endothelin-A receptor antagonist quality, caused only a modest elevation of PRL secretion in the control group. Endothelin antagonism did not affect PRL secretion in cells obtained from progesterone-implanted animals. Endothelin antagonism did, however, increase overall PRL secretion in the estradiol and estradiol plus progesterone groups by five- and threefold, respectively. Frequency distribution of PRL plaques in these same two BQ123-treated groups revealed two subpopulations, indicating that lactotrophs differ in their response to endogenous endothelin feedback and that this difference is steroid dependent. These observations clearly suggest that the ovarian steroid milieu (estrogens in particular) can have a profound influence on the self-regulatory mechanisms of lactotrophs. Our results also emphasize that endogenous endothelins may play an important role in the negative feedback regulation of PRL secretion in female rats.