Victoria Pocock

The Transcriptional Corepressor RIP140 Regulates Oxidative Metabolism in Skeletal Muscle

Summary Nuclear receptor signaling plays an important role in energy metabolism. In this study we demonstrate that the nuclear receptor corepressor RIP140 is a key regulator of metabolism in skeletal muscle. RIP140 is expressed in a fiber type-specific manner, and manipulation of its levels in null, heterozygous, and transgenic mice demonstrate that low levels promote while increased expression suppresses the formation of oxidative fibers. Expression profiling reveals global changes in the expression of genes implicated in both myofiber phenotype and metabolic functions. Genes involved in fatty-acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis are upregulated in the absence of RIP140. Analysis of cultured myofibers demonstrates that the changes in expression are intrinsic to muscle cells and that nuclear receptor-regulated genes are direct targets for repression by RIP140. Therefore RIP140 is an important signaling factor in the regulation of skeletal muscle function and physiology.

Assessment of estrogenic activity in some common essential oil constituents

Estrogenic responses have not only been associated with endocrine function, but also with cognitive function. Several studies have indicated that estrogen replacement therapy has favourable effects on cognition, and may have potential in the prevention and treatment of Alzheimers disease. Thus, ligands for the estrogen receptor, that have a better efficacy and adverse‐effect profile than drugs currently available, require investigation. This study was undertaken to investigate the potential estrogenic activity of a number of essential oil constituents. Initially, estrogenic activity was determined by a sensitive and specific bioassay using recombinant yeast cells expressing the human estrogen receptor. At high concentrations, estrogenic activity was detected for citral (geranial and neral), geraniol, nerol and trans‐anethole, while eugenol showed anti‐estrogenic activity. Molecular graphics studies were undertaken to identify the possible mechanisms for the interaction of geranial, neral, geraniol, nerol and eugenol with the ligand‐binding domain of the estrogen α‐receptor, using the computer program HyperChem. Citral, geraniol, nerol and eugenol were also able to displace [3H]17β‐estradiol from isolated α‐ and β‐human estrogen receptors, but none of these compounds showed estrogenic or anti‐estrogenic activity in the estrogen‐responsive human cell line Ishikawa Var I at levels below their cytotoxic concentrations, and none showed activity in a yeast screen for androgenic and anti‐androgenic activity. The potential in‐vivo estrogenic effects of citral and geraniol were examined in ovariectomized mice, but neither compound showed any ability to stimulate the characteristic estrogenic responses of uterine hypertrophy or acute increase in uterine vascular permeability. These results show that very high concentrations of some commonly used essential oil constituents appear to have the potential to interact with estrogen receptors, although the biological significance of this is uncertain.

Effects of perinatal octylphenol on ultrasound vocalization, behavior and reproductive physiology in rats

A rodent diet containing paraffin wax was designed to administer the environmental estrogen octylphenol (OP) to nonpregnant, pregnant and lactating rats. The estrogenic activity of OP via this diet was first confirmed in ovariectomized adult animals: 20 mg OP/kg/day increased the mitoses in the vaginal epithelium, and 60 mg OP/kg/day stimulated mitoses in the uterine luminal epithelium. The effects on a variety of reproductive and nonreproductive parameters were then investigated in the offspring of dams fed OP (100-250 mg/kg/day during gestation and lactation). A number of modest reproductive and morphological effects observed in the offspring including decreased body weights in adults of both sexes, disrupted vaginal cyclicity and decreases in seminiferous tubule diameter and testis, kidney, spleen and ovary weights. Behavioral effects included increased sexual arousal in males, increased sexual motivation in females towards a female teaser and increased motor activity by females. Ultrasonic vocalizations by pups at Postnatal Day (PND) 7 were reduced in number and duration in both sexes. There were no effects of perinatal OP on ano-genital distance, prepuce separation, aggressive behavior or adult ultrasound vocalization. These observations confirm that the dietary intake of estrogenic amounts of OP during pregnancy and lactation can have a wide variety of effects in the offspring.

Comparison of the oestrogenic effects of infant milk formulae, oestradiol and the phytoestrogen coumestrol delivered continuously in the drinking water to ovariectomised mice

The potential oestrogenic effects of infant milk formulae, coumestrol and oestradiol delivered in the drinking water were investigated in ovariectomised mice. None of the infant formulae tested (three soya, two cows milk) produced any uterotrophic or mitotic responses in the reproductive tract, although the soya milks displayed weak oestrogenic activity in vitro. Studies of the interactions between coumestrol and oestradiol were undertaken to investigate claims that phytoestrogens may act as oestrogen antagonists. The responses to coumestrol (100 g/ml drinking water) and 17-oestradiol (100 ng/ml) given separately were similar. Combined administration begun simultaneously produced only additive effects on uterine weight and cell proliferation in the vagina and uterus. While pretreatment with coumestrol for 24 h reduced the mitotic response of the uterus 48 h after placement of an oestradiol implant, the uterine weight increase was unaffected and the apparent reduction in mitoses reflected the natural fluctuations in the underlying cycle of cell proliferation. These studies indicate that coumestrol acts as a typical oestrogen and shows only additive effects with oestradiol. The results also indicate that infant soya milk formulae do not constitute a large enough source of oestrogenic compounds to invoke oestrogenic effects in the reproductive tract of mature mice.