Cameron Muir

Testicular degeneration in Huntington disease

Huntington disease (HD) is an adult onset, neurodegenerative disorder that results from CAG expansion in the HD gene. Recent work has demonstrated testicular degeneration in mouse models of HD and alterations in the hypothalamic-pituitary-gonadal (HPG) axis in HD patients. Here, we show that HD patients have specific testicular pathology with reduced numbers of germ cells and abnormal seminiferous tubule morphology. In the YAC128 mouse model, testicular degeneration develops prior to 12 months of age, but at 12 months, there is no evidence for decreased testosterone levels or loss of GnRH neurons in the hypothalamus. This suggests that testicular pathology results from a direct toxic effect of mutant huntingtin in the testis and is supported by the fact that huntingtin is highly expressed in the affected cell populations in the testis. Understanding the pathogenesis of HD in the testis may reveal common critical pathways which lead to degeneration in both the brain and testis.

Non-invasive repeated measurement of urinary progesterone, 17β-estradiol, and testosterone in developing, cycling, pregnant, and postpartum female mice

Excretory samples from adult female mice were collected non-invasively during development, estrous cycling, pregnancy, and postpartum. In initial studies, urinary measures were statistically more dynamic over days than were fecal measures; thus subsequent studies focused on urine. Higher 17beta-estradiol levels were present in isolated females than in those exposed to males. In cycling females, urinary 17beta-estradiol was more variable than were measures of testosterone or progesterone, showing peaks with an approximate 5-day periodicity. When urinary estradiol and progesterone were monitored in conjunction with vaginal smear cell counts, patterns were idiosyncratic; most females showed distinct peaks in urinary steroids, not in clear synchrony with vaginal cell cornification. Levels of progesterone rose markedly during the first 10 days of pregnancy, then declined before birth. Estradiol showed a substantial peak on days 7-8 of gestation in all females measured. Urinary testosterone was not dynamic during pregnancy, but rose in immediate prenatal and postpartum measures. During post-weaning, pre-pubertal development, urinary levels of progesterone remained constant but levels of estradiol rose substantially over time.

Peer Victimization, Depressive Symptoms, and High Salivary Cortisol Predict Poorer Memory in Children.

The predictive relations of peer victimization, depressive symptoms, and salivary cortisol on memory in 168 children aged 12 at Time 1 (T1) were examined using a longitudinal design in which data were collected on four occasions over a 2-year period. Results indicated that: (1) peer victimization, depressive symptoms, and evening cortisol were stable over time, (2) peer victimization and elevated symptoms of depression were concurrently linked at each time, (3) T1 peer victimization predicted elevated symptoms of depression at T2 which in turn predicted lower cortisol levels at T3, and (4) controlling for earlier associations, T3 peer victimization, depressive symptoms, and higher morning and evening cortisol levels uniquely predicted memory deficits at T4. The links between elevated cortisol, symptoms of depression, and poor memory are consistent with published research on depressed adults and extend the findings to children exposed to peer victimization. These findings highlight that peer abuse is harmful and may impact childrens long-term mental health and memory functioning.

Androgen dynamics in the context of children's peer relations: an examination of the links between testosterone and peer victimization

Testosterone levels have been shown to decrease in the face of social defeat in several mammalian species. Among humans, the loss of social status has been studied primarily in the context of athletic competition, with winners having higher testosterone levels than losers. This study examined testosterone levels in relation to peer victimization (bullying) in a sample of 151 boys and girls aged 12-13. Statistically controlling for age and pubertal status, results indicated that on average verbally bullied girls produced less testosterone and verbally bullied boys produced more testosterone than their nonbullied counterparts. Similar trends were evident comparing social and physical bullying with testosterone. Sex differences are discussed in terms of empirically validated differences in coping styles, as girls tend to internalize, whereas boys tend to externalize, their abuse.

Strange-male-induced pregnancy disruption in mice: Reduction of vulnerability by 17β-estradiol antibodies

It is well-established that novel males can disrupt early pregnancy in house mice. Inseminated female C57BL mice were either left undisturbed or each exposed indirectly to a novel HS male through a wire-mesh grid during days 1-6 of pregnancy. Varied dosages of antibodies to 17 beta-estradiol were administered to females exposed to males. Vehicle-treated females exposed to novel males showed fewer litters than did nonexposed controls. Male-exposed females given 1 ml daily of the antibody showed rates of pregnancy comparable to those observed in controls. These data suggest that estrogen levels might play a role in strange-male-induced pregnancy disruptions, converging with evidence implicating estrogens in stress-induced pregnancy blocks.

Pheromones and novel male-induced pregnancy disruptions in mice: exposure to conspecifics is necessary for urine alone to induce an effect.

Previous research indicates a role of pheromones in novel male-induced early pregnancy disruptions. Although some reports suggest that urine alone is sufficient to produce this effect, others raise procedural concerns and fail to replicate such effects. On Days 1 to 5 after insemination, female CF-1 mice had their nasal regions repeatedly painted with water, urine from males housed in isolation, or urine from males housed in proximity to females. Almost all (87.5%) of the control females delivered litters. There was a small nonsignificant reduction in proportion parturient (78.5%) among females exposed to urine of males housed without social contact. The proportion of females parturient (57.1%) after treatment with urine from males housed in proximity to females was significantly different from controls. The magnitude of the effect of socially stimulated male urine is substantially less than that recorded when males are housed directly above inseminated females separated by a wire-mesh grid. These data suggest that production of pregnancy-disrupting male pheromones is stimulated by contact with conspecifics.

Stress lowers the threshold dose at which bisphenol A disrupts blastocyst implantation, in conjunction with decreased uterine closure and e-cadherin

Exposure to stress can disrupt blastocyst implantation in inseminated female mice, and evidence implicates elevation of the females estrogen:progesterone ratio. Exposure to the xenoestrogen, bisphenol A (BPA) can also disrupt implantation. Undisturbed control female CF-1 mice were compared to other females that were exposed to predators (rats) across a wire-mesh grid during gestation days (GD) 1-4, a procedure that elevates corticosterone but does not on its own disrupt implantation in this genetic strain. They were concurrently exposed to varied doses of BPA that on their own were below the threshold dose sufficient to disrupt implantation. On GD 6, we measured the number of intrauterine implantation sites and extracted their uteri, which subsequently were stained and analyzed for uterine luminal area and epithelial cadherin (e-cadherin), a molecule that causes uterine closure and adhesion of blastocysts to the uterine epithelium. The combination of rat-exposure stress and BPA significantly disrupted implantation and increased uterine luminal area, whereas either manipulation on its own did not. E-cadherin was significantly reduced by exposure to BPA, positively correlated with the number of implantation sites, and inversely correlated with luminal area. BPA exposure was also associated with nonmonotonic perturbation of urinary corticosterone concentrations and increased urinary estradiol concentrations on GD 6. These data are consistent with a potential summation of stress-induced estrogen and xenoestrogen activity.

Enzyme Immunoassay of Testosterone, 17β-Estradiol, and Progesterone in Perspiration and Urine of Preadolescents and Young Adults: Exceptional Levels in Men's Axillary Perspiration

Enzyme immunoassays for testosterone, 17beta-estradiol, and progesterone were validated for human facial and axillary perspiration and compared to levels in urine. In study 1, these assays were applied to samples from preadolescent girls and boys and young women and men. Mens axillary perspiration contained substantially higher levels of steroids than seen in other substrates from men or in any sample from women, boys, and girls. Male axillary steroid levels were very variable across individuals, and on average they exceeded levels in facial perspiration by 90-fold for testosterone and 45-fold for estradiol. Mens urinary testosterone also exceeded urinary levels of the other subjects. In study 2, axillary perspiration, urine, and saliva were collected from young men. Substantial axillary levels of testosterone and estradiol were again observed. Correlations of the same hormone among the different substrates were generally very low, except for a small correlation between estradiol levels measured in axillary perspiration and urine in study 2. High unconjugated steroid content in mens axillary excretions could, if absorbed by women during intimacy, be implicated in pheromonal activity.

Intense arousal of novel male mice in proximity to previously inseminated females: Inactivation of males via chlorpromazine does not diminish the capacity to disrupt pregnancy

In the course of investigating early pregnancy disruptions by novel males, intense behavioral interactions and chemical emissions were observed among males housed in proximity to inseminated females. These interactions were evident despite wire-mesh separations between males and females. Experiments were designed to examine whether such arousal plays a role in pregnancy disruption. During the first 5 days of pregnancy, inseminated CF-1 strain female mice were either left undisturbed or exposed to novel outbred males. Physical separations between males did not diminish the frequency of pregnancy disruption. Subsequently, we investigated whether heavy sedation of novel males via chronic chlorpromazine administration would diminish the capacity to disrupt pregnancy. Pregnancy was disrupted to the same degree in females exposed to drug-treated males and those exposed to alert competing males given vehicle injections. These data show an unprecedented degree of arousal and pheromonal emission among competing males but suggest that these factors are not critical for the capacity to disrupt pregnancy.

Differential sexual activity of isolated and group-housed male mice : Lack of substantial influence of acute or chronic naloxone administration

Influences of naloxone upon male sexual behavior were examined using two different baseline activity levels: individually and group-housed mice. In Experiment 1, single injections of 0,12.5, or 50 micrograms per animal were administered before testing. Isolated mice showed more sexual activity than did grouped mice; naloxone failed to alter those differences. In Experiment 2, a similar result was obtained despite administration of 50 or 150 micrograms per animal of naloxone. In Experiment 3,0 or 50 micrograms of naloxone was administered to isolated or grouped males daily on the 5 days before testing. Isolated mice showed performance superior to that of grouped mice, but there was no effect of the drug. In Experiment 4, doses of 0. 12.5, or 50 micrograms of naloxone were given to isolated or grouped males twice daily for 7 days prior to testing, producing little effect. These results suggest that the influences of prior social condition on male sexual activity are robust in the face of naloxone administration.