The invention of electric light has facilitated a society in which people work, sleep, eat, and play at all hours of the 24-hour day. Although electric light clearly has benefited humankind, exposures to electric light, especially light at night (LAN), may disrupt sleep and biological processes controlled by endogenous circadian clocks, potentially resulting in adverse health outcomes. Many of the studies evaluating adverse health effects have been conducted among night- and rotating-shift workers, because this scenario gives rise to significant exposure to LAN. Because of the complexity of this topic, the National Toxicology Program convened an expert panel at a public workshop entitled "Shift Work at Night, Artificial Light at Night, and Circadian Disruption" to obtain input on conducting literature-based health hazard assessments and to identify data gaps and research needs. The Panel suggested describing light both as a direct effector of endogenous circadian clocks and rhythms and as an enabler of additional activities or behaviors that may lead to circadian disruption, such as night-shift work and atypical and inconsistent sleep-wake patterns that can lead to social jet lag. Future studies should more comprehensively characterize and measure the relevant light-related exposures and link these exposures to both time-independent biomarkers of circadian disruption and biomarkers of adverse health outcomes. This information should lead to improvements in human epidemiological and animal or in vitro models, more rigorous health hazard assessments, and intervention strategies to minimize the occurrence of adverse health outcomes due to these exposures.

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The ovariectomized (OVX), lactating rat model has been used to investigate the skeletal effects of the plant estrogen, genistein, over a 14-day period. The OVX, lactating rat on a low-calcium diet loses slightly more than 50% of its bone mineral mass during the first 2 weeks of lactation, and we have demonstrated that estrogen treatment can significantly reduce the loss of femoral mass (ash weight). Following OVX, the rats were assigned to treatment or control groups (both placebo and positive control with estrogen replacement). The treatment groups received one of three doses of a genistein-rich preparation each day via the feed for 2 weeks, after which time the pups began to have an interest in solid feed. A positive control group received conjugated estrogen in the feed. The genistein doses were: low (0.5 mg/d); intermediate (1.6 mg/d); and high (5.0 mg/d). Measurements included ash weights of the femur, scanning electron microscopy (SEM) of the proximal tibia, and uterine weights. SEM results were as follows: (1) at the low dose genistein was approximately equally effective to estrogen in the retention of cancellous bone tissue, as reflected in the number and density of trabeculae in hemisections of the tibial subepiphyseal region, but at high doses genistein was less effective; and (2) rats treated with low-dose genistein, like estradiol, had rougher endosteal surfaces and smaller pores on these surfaces than untreated control rats. Mean ash weights of the entire femur were highest in the rats treated with the low dose compared to control rats (P < 0.05), and they were higher than ash weights of rats administered the intermediate or high doses of genistein. The mean ash weights of the femurs were consistent with the genistein effects on the tibias observed by SEM. In summary, a biphasic response to the genistein preparation was found in this OVX rat model. Interpretation of the results suggests that, at the low dose, genistein appears to be an agonist at the estrogen receptor locus, whereas at higher doses the genistein is less effective and may even have adverse effects on bone cells. These findings of a biphasic effect of genistein (i.e., an inverted U effect) are consistent with those of other recent reports in the literature on isolated bone cells and on reproductive tissues. In summary, lower doses of genistein from soy foods would be expected to act similarly to estrogens with a beneficial effect on bone tissue, but at high doses that are unlikely to be consumed in human diets, this soy derivative may have potentially adverse effects on bone cell functions and thereby on bone tissue.

We isolated osteoblastic cell lines from wild-type (CasR ؉/؉ ) and receptor null (CasR ؊/؊ ) mice to investigate whether CasR is present in osteoblasts and accounts for their responses to extracellular cations. Osteoblasts from both CasR ؉/؉ and CasR ؊/؊ mice displayed an initial period of cell replication followed by a culture duration-dependent increase in alkaline phosphatase activity, expression of osteocalcin, and mineralization of extracellular matrix. In addition, a panel of extracellular cations, including aluminum and the CasR agonists gadolinium and calcium, stimulated DNA synthesis, activated a transfected serum response elementluciferase reporter construct, and inhibited agonistinduced cAMP in CasR ؊/؊ osteoblasts. The functional responses to these cations were identical in CasR ؉/؉ and CasR ؊/؊ osteoblasts. Thus, the absence of CasR alters neither the maturational profile of isolated osteoblast cultures nor their in vitro responses to extracellular cations. In addition, CasR transcripts could not be detected by reverse transcription-polymerase chain reaction with mouse specific primers in either CasR ؉/؉ or CasR ؊/؊ osteoblasts, and immunoblot analysis with a CasR-specific antibody was negative for CasR protein expression in osteoblasts. The presence of a cation-sensing response in osteoblasts from CasR ؊/؊ mice indicates the existence of a novel osteoblastic extracellular cation-sensing mechanism.

Objective: To review the current literature on the effects of soy isoflavones, one class of phyto-oestrogens, on cardiovascular diseases, osteoporosis, cancer and climacteric symptoms. Design: Many study designs were employed in the reports reviewed here, including prospective human trials, observational human studies, animal experiments and in vitro cell studies that explored the protective or preventive effects of soy isoflavones (genistein, daidzein and glycitein alone or mixed). Setting: Diverse settings were employed, depending on study design. Subjects: Human subjects, mostly menopausal or postmenopausal, were included, as were animal models and specific cell types. Results: The findings were: (i) isoflavones plus soy protein together were needed to obtain the highly significant beneficial results on blood lipids and arterial dimensions; (ii) isoflavone treatments alone at high doses (relative to above) consistently improved bone parameters in rodent ovariectomized models, but not in humans or primates; (iii) isoflavones were not consistent in exerting positive effects regarding the prevention or treatment of cancers of the mammary glands, uterus and colon; and (iv) the effects of isoflavones on climacteric symptoms were not clear-cut. Conclusions:The promise of soy isoflavones reducing chronic disease risk seems to be non-uniform, with the most conclusive benefits occurring in the prevention of cardiovascular diseases, but other organ systems, such as skeletal and reproductive tissues, may also benefit from the consumption of soy and soy-derived products. Phyto-oestrogenic molecules have received a great deal of attention over the last few years because of their potentially preventive roles against a few of today's most prevalent chronic diseases, namely, cardiovascular disease, osteoporosis and hormone-related cancers 1,2 . The particular plant molecules of interest are isoflavones, which are found in abundance in soybeans and their derivative foods, such as tofu, miso and others. Of the several isoflavones that are made by soybeans, genistein, in particular, has been experimentally shown to be the most efficacious in human subjects and animal models. For the last several years, a concerted effort has been mounted to identify alternatives to traditional hormone replacement therapy (HRT). Pharmaceutical companies have been developing selective oestrogen receptor modulators (SERMs), which ideally will provide the beneficial effects of oestrogen replacement for bones, cardiovascular system and cognitive function, without adverse effects on breast and endometrial cancer. As a result, SERMs should not require co-administration with a progestin, which can eliminate the side effects that some women experience with that hormone. The first molecules of this new class of drugs to become available are tamoxifen and raloxifene, which exhibit many, but not all, of the qualities of an ideal HRT. Many consumers would also prefer to avoid synthetic molecules in favour of natural products. Soy phytooestrogens, na...

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