Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levo... more Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys (Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17b-estradiol (E 2 ), (3) 0.5 mg/kg levormeloxifene (L 1 ), (4) 1.0 mg/kg levormeloxifene (L 2 ), and (5) 5.0 mg/kg levormeloxifene (L 3 ). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo (p < .0001 for all). The target dose of levormeloxifene (L 2 ) resulted in higher serum concentrations of cortisol (þ63%), dehydroepiandrosterone-sulfate (þ73%), and androstenedione (þ37%) compared with the placebo group (p < .05 for all). In contrast, E 2 resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E 2 and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo (p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E 2 , may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.
In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Mac... more In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Macaca fascicularis), we compared monkeys that were given either placebo (OVX, n = 26) or 17b estradiol (E 2 ) (EST, n = 26) in a daily oral dose. Serum cortisol concentrations were measured prior to the experimental manipulation and 3, 6, 9, and 12 months following initiation of treatment. Pretreatment cortisol values did not differ between groups. Assessment of the treatment period values revealed that cortisol concentrations were significantly higher (E10%) in the EST than in the OVX monkeys. Cortisol also varied significantly across periods of sampling. This time-dependent variation was attributable to elevations in months 6 and 9 (when daylight was generally long), relative to months 3 and 12 (when daylight was relatively short). The modest stimulatory effect of estrogen on corticosteroid production observed in this study is consistent with what has been seen in women, and contrasts with the more robust effects observed in New World monkeys. The possible relationship between season and cortisol secretion observed here has not been previously described in monkeys. Am. J.
The relationships among social rank, basal cortisol concentrations, and social behavior were asse... more The relationships among social rank, basal cortisol concentrations, and social behavior were assessed in adult female cynomolgus monkeys (Macaca fascicularis). Subjects were 157 unrelated, reproductively intact animals housed in 30 small groups. Rank determinations were made monthly. Blood samples were collected on two occasions, 4.5 and 7.5 months following initial group formation. Regular behavioral observations were conducted on a subset of animals over a period of 4 weeks, 9 months following group formation. Analyses revealed that serum cortisol values were significantly correlated across the two sampling periods, with no significant change in absolute values. While social rank was positively correlated across both samples, there was no relationship between rank and cortisol. However, dominant and subordinate animals did differ in the rates of performance of aggressive and submissive behaviors. These data suggest that social rank does not influence baseline serum cortisol in adult female cynomolgus monkeys, despite stability in measures of rank and cortisol and the presence of the usual behavioral differences between dominants and subordinates.
Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated ... more Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.
Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were ev... more Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were evaluated as an index of elevated bone turnover following ovariectomy. The enzyme immunoassay 96-well microtiter plate B-ALP assay, developed by Metra Biosystems (Mountain View, CA) for human use, was employed and compared with a standard automated assay measuring total serum levels of alkaline phosphatase activity (T-ALP). The B-ALP assay was first validated for use in these monkeys. Ovariectomy led to increased bone turnover as indicated by approximately 2-fold higher activity in both assays and this elevation was inhibited by daily estradiol administration. Although both assays provided generally similar results, several monkeys were observed to have greatly elevated values of T-ALP but not B-ALP. This discrepancy is believed to result from high levels of the liver isoform of alkaline phosphatase in monkeys with hepatic dysfunction, which are not detected by the B-ALP assay.
Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were ev... more Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were evaluated as an index of elevated bone turnover following ovariectomy. The enzyme immunoassay 96-well microtiter plate B-ALP assay, developed by Metra Biosystems (Mountain View, CA) for human use, was employed and compared with a standard automated assay measuring total serum levels of alkaline phosphatase activity (T-ALP). The B-ALP assay was first validated for use in these monkeys. Ovariectomy led to increased bone turnover as indicated by approximately 2-fold higher activity in both assays and this elevation was inhibited by daily estradiol administration. Although both assays provided generally similar results, several monkeys were observed to have greatly elevated values of T-ALP but not B-ALP. This discrepancy is believed to result from high levels of the liver isoform of alkaline phosphatase in monkeys with hepatic dysfunction, which are not detected by the B-ALP assay.
We examined the effects of chronic social stress and social rank on monoamine concentrations in t... more We examined the effects of chronic social stress and social rank on monoamine concentrations in the prefrontal cortex (PFC) in adult male cynomolgus macaques (Macaca fascicularis). Seventy-five animals were housed in five-member social groups for 28 months and were exposed to three experimental conditions. A 'no-stress' condition was comprised of animals housed in groups of stable membership throughout the study. Animals assigned to a 'past-stress' condition had their group memberships reorganized at monthly intervals during the first (but not last) 14 months of the study, and a third 'recent-stress' condition consisted of social groups reorganized only during the last 14 months. At necropsy, the brains were collected and frozen at -70°C until analyzed. Prefrontal orbital cortex was assayed for monoamines (serotonin (5-HT), dopamine (DA), norepinephrine (NE)), metabolites (5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenethyleneglycol (MHPG)), and tryptophan using high-performance liquid chromatography with electrochemical detection. Animals in the past-stress condition had significantly lower PFC 5-HIAA concentrations compared to those in the no-stress condition (P < 0.05). PFC 5-HT concentrations of animals in the past-stress condition were significantly lower than those in the no-stress and recent-stress conditions (P < 0.01). The concentrations of DA, HVA, NE and MHPG were not altered. These data suggest that exposure to chronic social stress is associated with long-term selective reductions in serotonergic activity in the PFC. This effect may underlie the association in human beings between reduced serotonergic function and conditions such as pathological grief and posttraumatic stress disorder.
Female cynomolgus monkeys, a previously established model of carotid and coronary artery atherosc... more Female cynomolgus monkeys, a previously established model of carotid and coronary artery atherosclerosis, were used to study the relationships between poten- tial risk factors and carotid artery atherosclerosis. Over a 24-month treatment period, one-third of the monkeys (n=25) were given the oral contraceptive Ovral, one-third of the monkeys (n=26) were given the oral contraceptive Demulen, and the remaining monkeys constituted
Specific genotypes of the rhesus monkey and human serotonin transporter gene (SERT) promoter regi... more Specific genotypes of the rhesus monkey and human serotonin transporter gene (SERT) promoter region are associated with personality traits and serotonergic activity. However, the most commonly studied promoter polymorphism (5-HTTLPR) is monomorphic in many other monkey species. To date, no systematic search for alternative potentially functional polymorphisms across the remaining coding parts of the gene has been undertaken in other
Comparatively little is known about the pathways of proximate causation that link divergent genot... more Comparatively little is known about the pathways of proximate causation that link divergent genotypes, via neurophysiological differences, to distinct, species-specific social behaviors and systems. One approach to the problem compares gross activity levels of monoamine neurotransmitters (norepinephrine, dopamine, and serotonin), evidenced by their metabolites —3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively— in cerebrospinal fluid (CSF). We have applied this method to Papio hamadryas and P. anubis, closely related baboon species with divergent social behavior, living in the Awash National Park (ANP), Ethiopia. We had previously shown that adult males of the two species differ in the ratio of HVA to 5-HIAA, and in concentrations of MHPG and HVA, but not 5-HIAA. Here, we compare monoamine metabolite levels of the parental species with those of 49 members of a naturally formed, multigenerational hamadryas × anubis ...
To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (2... more To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (25(OH)D(3)) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C). One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3-25 years consumed a typical western diet for 7-8 weeks that provided a woman's equivalent of approximately 1000 IU/day of vitamin D(3). Measurements of vitamin D(3) and HDL-C concentrations, as well as waist circumference, were obtained. Among young monkeys (aged 3-5 years), compared to older monkeys (aged 16-25 years), the mean plasma 25(OH)D(3) concentrations were 82.3±3.2 ng/mL and 58.6±2.9 ng/mL (p<0.0001), respectively. Plasma 25(OH)D(3) concentrations had a range of 19.6-142.0 ng/mL (mean±standard error [SE] 66.4±1.7 ...
The aim of this study was to analyze coronary artery vitamin D receptor (VDR) expression, the pla... more The aim of this study was to analyze coronary artery vitamin D receptor (VDR) expression, the plasma concentrations of 25-hydroxyvitamin D3 (25OHD3), and their relationship with coronary artery atherosclerosis. Premenopausal cynomolgus monkeys were fed atherogenic diets containing the equivalent of 1,000 IU/day of vitamin D3. Protein was derived from casein-lactalbumin (C/L, n = 10), soy protein isolate (soy, n = 10), or a combination (n = 19). After 32 months of consuming the diets, each monkey underwent surgical menopause. After 32 postmenopausal months, coronary atherosclerosis was measured in the left circumflex (LCX) artery and left anterior descending (LAD) artery. VDR expression was determined for the LAD, and 25OHD3 concentrations were assessed. Both the cross-sectional area of atherosclerotic plaques (in square millimeters) and plaque thickness (in millimeters) in the LCX as well as the LAD arteries were analyzed in these monkeys. Those with higher plasma vitamin D3 concent...
OBJECTIVE: The aim of this study was to determine if premenopausal ovarian reserve is associated ... more OBJECTIVE: The aim of this study was to determine if premenopausal ovarian reserve is associated with susceptibility for atherosclerosis. METHODS: Female cynomolgus macaques (n = 66, women's equivalent age = 45 y) consumed an atherogenic diet for ∼5 months before the measurement of a marker of ovarian reserve (antimüllerian hormone [AMH]), plasma lipids, follicular phase estradiol, and body weight (BW). Monkeys were then ovariectomized (OVX; n = 17), remained premenopausal (n = 20), or were induced to have reduced ovarian reserve (ROR, n = 29). After 26 additional months consuming the diet, atherosclerosis measurements and risk variables were reassessed. RESULTS: No differences in baseline AMH, plasma lipids, BW, and estradiol or postdiet lipids and BW were observed among the groups subsequently assigned to the OVX, premenopausal control, or reduced ovarian reserve conditions. Postdiet measurements of atherosclerosis extent did not differ among the groups. However, analysis of p...
Soy isoflavones are commonly used to alleviate menopause-related symptoms. Postmenopausal women a... more Soy isoflavones are commonly used to alleviate menopause-related symptoms. Postmenopausal women are at increased risk for hypothyroidism, and there are concerns that isoflavones may be detrimental to thyroid health. The aim of this study was to examine the effects of soy protein and isoflavones on thyroid function and the relationship between thyroid function and ovarian function. Adult female cynomolgus monkeys (Macaca fascicularis) were randomized to consume two diets differing only in protein source: casein-lactalbumin (n = 44) or soy protein with isoflavones (n = 41). After 34 months, all animals were ovariectomized via laparotomy. Half of the monkeys from each diet treatment group continued to consume their preovariectomy treatment phase diet (either isolated soy protein [n = 19] or casein-lactalbumin [n = 21]) for an additional 34 months. The remaining animals did not continue their diets and thus were not considered further. Circulating progesterone, triiodothyronine, thyroxi...
The objective of this study was to use a well-established monkey model of atherosclerosis to dete... more The objective of this study was to use a well-established monkey model of atherosclerosis to determine how life stage and preexisting atherosclerosis influence the effectiveness of high-isoflavone soy diet in inhibiting progression of atherosclerosis.
The activated vitamin D receptor (VDR) may have an important role in vascular health. The objecti... more The activated vitamin D receptor (VDR) may have an important role in vascular health. The objective of this study was to determine whether there is an association between the expression of VDRs in coronary arteries and the extent of diet-induced atherosclerosis. Utilizing a cohort of 39 postmenopausal female cynomolgus monkeys with varying stages of atherosclerosis, histologic sections of the left anterior descending artery (LAD) were analyzed for plaque cross-sectional area, plaque thickness, and VDR quantity using immunohistochemical H-score analysis. The quantities of VDRs were analyzed as a continuous variable and were divided at the median intimal H-score into high vs. low groupings. In the LAD, a significant negative correlation was observed between the quantity of VDR and plaque size (both cross-sectional area [p<0.001] and plaque thickness [p<0.001]). Monkeys in the low VDR group had a significantly greater cross-sectional plaque area (1.2mm(2)) and greater plaque thic...
The vervet is an old world monkey increasingly being used as a model for human diseases. In addit... more The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer's disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that with changes in NA levels and astrocyte activation. Total amyloid beta (Aβ)40 and Aβ42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aβ42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased glial fibrillary acidic protein staining and messenger RNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aβ42 and Aβ40, and the number of 6E10-positive plaques, were correlated with NA levels. Interestingly messenger RNA levels of glial derived neurotrophic factor, important for n...
Journal of the American Association for Laboratory Animal Science: JAALAS
Our goal was to assess a nonhuman primate diet that mimicked the Western-type diet of humans with... more Our goal was to assess a nonhuman primate diet that mimicked the Western-type diet of humans with regard to palatability and the diet's effects on plasma lipid concentrations and other cardiometabolic risk factors. We evaluated male (n = 8) and female (n = 11) African green monkeys (vervets; Chlorocebus aethiops sabaeus) that initially were fed a standard diet. Each cohort then was divided into 2 groups, which received either standard chow or the Western diet. Food consumption and fecal quality were measured weekly. Body weight, waist circumference, and body-mass index were measured every 2 wk. CBC and clinical chemistry analyses were performed at baseline and 4 wk after the diet change. Plasma lipid concentrations, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, insulin, and fructosamine were measured at baseline and at 4, 8, and 12 wk after the diet change. Isoflavones were measured in the male monkeys at 6 wk after diet change, and lipid particle ...
Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levo... more Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys (Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17b-estradiol (E 2 ), (3) 0.5 mg/kg levormeloxifene (L 1 ), (4) 1.0 mg/kg levormeloxifene (L 2 ), and (5) 5.0 mg/kg levormeloxifene (L 3 ). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo (p < .0001 for all). The target dose of levormeloxifene (L 2 ) resulted in higher serum concentrations of cortisol (þ63%), dehydroepiandrosterone-sulfate (þ73%), and androstenedione (þ37%) compared with the placebo group (p < .05 for all). In contrast, E 2 resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E 2 and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo (p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E 2 , may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.
In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Mac... more In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Macaca fascicularis), we compared monkeys that were given either placebo (OVX, n = 26) or 17b estradiol (E 2 ) (EST, n = 26) in a daily oral dose. Serum cortisol concentrations were measured prior to the experimental manipulation and 3, 6, 9, and 12 months following initiation of treatment. Pretreatment cortisol values did not differ between groups. Assessment of the treatment period values revealed that cortisol concentrations were significantly higher (E10%) in the EST than in the OVX monkeys. Cortisol also varied significantly across periods of sampling. This time-dependent variation was attributable to elevations in months 6 and 9 (when daylight was generally long), relative to months 3 and 12 (when daylight was relatively short). The modest stimulatory effect of estrogen on corticosteroid production observed in this study is consistent with what has been seen in women, and contrasts with the more robust effects observed in New World monkeys. The possible relationship between season and cortisol secretion observed here has not been previously described in monkeys. Am. J.
The relationships among social rank, basal cortisol concentrations, and social behavior were asse... more The relationships among social rank, basal cortisol concentrations, and social behavior were assessed in adult female cynomolgus monkeys (Macaca fascicularis). Subjects were 157 unrelated, reproductively intact animals housed in 30 small groups. Rank determinations were made monthly. Blood samples were collected on two occasions, 4.5 and 7.5 months following initial group formation. Regular behavioral observations were conducted on a subset of animals over a period of 4 weeks, 9 months following group formation. Analyses revealed that serum cortisol values were significantly correlated across the two sampling periods, with no significant change in absolute values. While social rank was positively correlated across both samples, there was no relationship between rank and cortisol. However, dominant and subordinate animals did differ in the rates of performance of aggressive and submissive behaviors. These data suggest that social rank does not influence baseline serum cortisol in adult female cynomolgus monkeys, despite stability in measures of rank and cortisol and the presence of the usual behavioral differences between dominants and subordinates.
Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated ... more Levormeloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), has been evaluated for its effects on bone in cynomolgus monkeys (Macaca fascicularis). Adult female monkeys were imported from Indonesia and randomized into six groups of 25-28 animals each (n = 158). Animals in one group were sham ovariectomized (sham) and received vehicle. Animals in the remaining five groups were ovariectomized and received either vehicle (ovx); 17beta-estradiol at 0.016 mg/kg (est); or levormeloxifene at 0.5 (L1), 1 (L2), or 5 (L3) mg/kg. Lumbar spine and whole body bone mass were measured by dual-energy X-ray absorptiometry (DXA) pretreatment and at 6 and 12 months following the initiation of treatment. Bone mass at the femoral neck was measured by peripheral quantitative computed tomography (pQCT) at 0 and 12 months. Serum markers of bone turnover, including bone-specific alkaline phosphatase (BSAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary collagen C-terminal extension peptides (CrossLaps), were measured at 0, 6, and 12 months. Ovariectomy resulted in an increase in these markers; the increase was prevented by estradiol or levormeloxifene. Estradiol or levormeloxifene inhibited loss of lumbar spine bone mineral density (BMD) following ovariectomy compared with untreated monkeys (ovx -5.0%; sham -0.4%; est +0.2%; L1 -3.6%, L2 -2.0%, L3 -2.5%). Estradiol, but not levormeloxifene, prevented loss of BMD at the femoral neck (ovx -7.4%; sham -3.1%; est -3.6%; L1 -8.0%, L2 -6.5%, L3 -7.8%), and whole body bone mineral content (BMC) (ovx -7.6%; sham -1.9%, est -2.9%; L1 -6.2%, L2 -6.1%, L3 -6.7%). Bone loss at each site was correlated with bone turnover as measured by serum and urine biomarkers. There was no dose effect of levormeloxifene.
Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were ev... more Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were evaluated as an index of elevated bone turnover following ovariectomy. The enzyme immunoassay 96-well microtiter plate B-ALP assay, developed by Metra Biosystems (Mountain View, CA) for human use, was employed and compared with a standard automated assay measuring total serum levels of alkaline phosphatase activity (T-ALP). The B-ALP assay was first validated for use in these monkeys. Ovariectomy led to increased bone turnover as indicated by approximately 2-fold higher activity in both assays and this elevation was inhibited by daily estradiol administration. Although both assays provided generally similar results, several monkeys were observed to have greatly elevated values of T-ALP but not B-ALP. This discrepancy is believed to result from high levels of the liver isoform of alkaline phosphatase in monkeys with hepatic dysfunction, which are not detected by the B-ALP assay.
Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were ev... more Serum levels of bone-specific alkaline phosphatase activity (B-ALP) in cynomolgus monkeys were evaluated as an index of elevated bone turnover following ovariectomy. The enzyme immunoassay 96-well microtiter plate B-ALP assay, developed by Metra Biosystems (Mountain View, CA) for human use, was employed and compared with a standard automated assay measuring total serum levels of alkaline phosphatase activity (T-ALP). The B-ALP assay was first validated for use in these monkeys. Ovariectomy led to increased bone turnover as indicated by approximately 2-fold higher activity in both assays and this elevation was inhibited by daily estradiol administration. Although both assays provided generally similar results, several monkeys were observed to have greatly elevated values of T-ALP but not B-ALP. This discrepancy is believed to result from high levels of the liver isoform of alkaline phosphatase in monkeys with hepatic dysfunction, which are not detected by the B-ALP assay.
We examined the effects of chronic social stress and social rank on monoamine concentrations in t... more We examined the effects of chronic social stress and social rank on monoamine concentrations in the prefrontal cortex (PFC) in adult male cynomolgus macaques (Macaca fascicularis). Seventy-five animals were housed in five-member social groups for 28 months and were exposed to three experimental conditions. A 'no-stress' condition was comprised of animals housed in groups of stable membership throughout the study. Animals assigned to a 'past-stress' condition had their group memberships reorganized at monthly intervals during the first (but not last) 14 months of the study, and a third 'recent-stress' condition consisted of social groups reorganized only during the last 14 months. At necropsy, the brains were collected and frozen at -70°C until analyzed. Prefrontal orbital cortex was assayed for monoamines (serotonin (5-HT), dopamine (DA), norepinephrine (NE)), metabolites (5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenethyleneglycol (MHPG)), and tryptophan using high-performance liquid chromatography with electrochemical detection. Animals in the past-stress condition had significantly lower PFC 5-HIAA concentrations compared to those in the no-stress condition (P < 0.05). PFC 5-HT concentrations of animals in the past-stress condition were significantly lower than those in the no-stress and recent-stress conditions (P < 0.01). The concentrations of DA, HVA, NE and MHPG were not altered. These data suggest that exposure to chronic social stress is associated with long-term selective reductions in serotonergic activity in the PFC. This effect may underlie the association in human beings between reduced serotonergic function and conditions such as pathological grief and posttraumatic stress disorder.
Female cynomolgus monkeys, a previously established model of carotid and coronary artery atherosc... more Female cynomolgus monkeys, a previously established model of carotid and coronary artery atherosclerosis, were used to study the relationships between poten- tial risk factors and carotid artery atherosclerosis. Over a 24-month treatment period, one-third of the monkeys (n=25) were given the oral contraceptive Ovral, one-third of the monkeys (n=26) were given the oral contraceptive Demulen, and the remaining monkeys constituted
Specific genotypes of the rhesus monkey and human serotonin transporter gene (SERT) promoter regi... more Specific genotypes of the rhesus monkey and human serotonin transporter gene (SERT) promoter region are associated with personality traits and serotonergic activity. However, the most commonly studied promoter polymorphism (5-HTTLPR) is monomorphic in many other monkey species. To date, no systematic search for alternative potentially functional polymorphisms across the remaining coding parts of the gene has been undertaken in other
Comparatively little is known about the pathways of proximate causation that link divergent genot... more Comparatively little is known about the pathways of proximate causation that link divergent genotypes, via neurophysiological differences, to distinct, species-specific social behaviors and systems. One approach to the problem compares gross activity levels of monoamine neurotransmitters (norepinephrine, dopamine, and serotonin), evidenced by their metabolites —3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively— in cerebrospinal fluid (CSF). We have applied this method to Papio hamadryas and P. anubis, closely related baboon species with divergent social behavior, living in the Awash National Park (ANP), Ethiopia. We had previously shown that adult males of the two species differ in the ratio of HVA to 5-HIAA, and in concentrations of MHPG and HVA, but not 5-HIAA. Here, we compare monoamine metabolite levels of the parental species with those of 49 members of a naturally formed, multigenerational hamadryas × anubis ...
To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (2... more To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (25(OH)D(3)) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C). One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3-25 years consumed a typical western diet for 7-8 weeks that provided a woman's equivalent of approximately 1000 IU/day of vitamin D(3). Measurements of vitamin D(3) and HDL-C concentrations, as well as waist circumference, were obtained. Among young monkeys (aged 3-5 years), compared to older monkeys (aged 16-25 years), the mean plasma 25(OH)D(3) concentrations were 82.3±3.2 ng/mL and 58.6±2.9 ng/mL (p<0.0001), respectively. Plasma 25(OH)D(3) concentrations had a range of 19.6-142.0 ng/mL (mean±standard error [SE] 66.4±1.7 ...
The aim of this study was to analyze coronary artery vitamin D receptor (VDR) expression, the pla... more The aim of this study was to analyze coronary artery vitamin D receptor (VDR) expression, the plasma concentrations of 25-hydroxyvitamin D3 (25OHD3), and their relationship with coronary artery atherosclerosis. Premenopausal cynomolgus monkeys were fed atherogenic diets containing the equivalent of 1,000 IU/day of vitamin D3. Protein was derived from casein-lactalbumin (C/L, n = 10), soy protein isolate (soy, n = 10), or a combination (n = 19). After 32 months of consuming the diets, each monkey underwent surgical menopause. After 32 postmenopausal months, coronary atherosclerosis was measured in the left circumflex (LCX) artery and left anterior descending (LAD) artery. VDR expression was determined for the LAD, and 25OHD3 concentrations were assessed. Both the cross-sectional area of atherosclerotic plaques (in square millimeters) and plaque thickness (in millimeters) in the LCX as well as the LAD arteries were analyzed in these monkeys. Those with higher plasma vitamin D3 concent...
OBJECTIVE: The aim of this study was to determine if premenopausal ovarian reserve is associated ... more OBJECTIVE: The aim of this study was to determine if premenopausal ovarian reserve is associated with susceptibility for atherosclerosis. METHODS: Female cynomolgus macaques (n = 66, women's equivalent age = 45 y) consumed an atherogenic diet for ∼5 months before the measurement of a marker of ovarian reserve (antimüllerian hormone [AMH]), plasma lipids, follicular phase estradiol, and body weight (BW). Monkeys were then ovariectomized (OVX; n = 17), remained premenopausal (n = 20), or were induced to have reduced ovarian reserve (ROR, n = 29). After 26 additional months consuming the diet, atherosclerosis measurements and risk variables were reassessed. RESULTS: No differences in baseline AMH, plasma lipids, BW, and estradiol or postdiet lipids and BW were observed among the groups subsequently assigned to the OVX, premenopausal control, or reduced ovarian reserve conditions. Postdiet measurements of atherosclerosis extent did not differ among the groups. However, analysis of p...
Soy isoflavones are commonly used to alleviate menopause-related symptoms. Postmenopausal women a... more Soy isoflavones are commonly used to alleviate menopause-related symptoms. Postmenopausal women are at increased risk for hypothyroidism, and there are concerns that isoflavones may be detrimental to thyroid health. The aim of this study was to examine the effects of soy protein and isoflavones on thyroid function and the relationship between thyroid function and ovarian function. Adult female cynomolgus monkeys (Macaca fascicularis) were randomized to consume two diets differing only in protein source: casein-lactalbumin (n = 44) or soy protein with isoflavones (n = 41). After 34 months, all animals were ovariectomized via laparotomy. Half of the monkeys from each diet treatment group continued to consume their preovariectomy treatment phase diet (either isolated soy protein [n = 19] or casein-lactalbumin [n = 21]) for an additional 34 months. The remaining animals did not continue their diets and thus were not considered further. Circulating progesterone, triiodothyronine, thyroxi...
The objective of this study was to use a well-established monkey model of atherosclerosis to dete... more The objective of this study was to use a well-established monkey model of atherosclerosis to determine how life stage and preexisting atherosclerosis influence the effectiveness of high-isoflavone soy diet in inhibiting progression of atherosclerosis.
The activated vitamin D receptor (VDR) may have an important role in vascular health. The objecti... more The activated vitamin D receptor (VDR) may have an important role in vascular health. The objective of this study was to determine whether there is an association between the expression of VDRs in coronary arteries and the extent of diet-induced atherosclerosis. Utilizing a cohort of 39 postmenopausal female cynomolgus monkeys with varying stages of atherosclerosis, histologic sections of the left anterior descending artery (LAD) were analyzed for plaque cross-sectional area, plaque thickness, and VDR quantity using immunohistochemical H-score analysis. The quantities of VDRs were analyzed as a continuous variable and were divided at the median intimal H-score into high vs. low groupings. In the LAD, a significant negative correlation was observed between the quantity of VDR and plaque size (both cross-sectional area [p<0.001] and plaque thickness [p<0.001]). Monkeys in the low VDR group had a significantly greater cross-sectional plaque area (1.2mm(2)) and greater plaque thic...
The vervet is an old world monkey increasingly being used as a model for human diseases. In addit... more The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer's disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that with changes in NA levels and astrocyte activation. Total amyloid beta (Aβ)40 and Aβ42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aβ42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased glial fibrillary acidic protein staining and messenger RNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aβ42 and Aβ40, and the number of 6E10-positive plaques, were correlated with NA levels. Interestingly messenger RNA levels of glial derived neurotrophic factor, important for n...
Journal of the American Association for Laboratory Animal Science: JAALAS
Our goal was to assess a nonhuman primate diet that mimicked the Western-type diet of humans with... more Our goal was to assess a nonhuman primate diet that mimicked the Western-type diet of humans with regard to palatability and the diet's effects on plasma lipid concentrations and other cardiometabolic risk factors. We evaluated male (n = 8) and female (n = 11) African green monkeys (vervets; Chlorocebus aethiops sabaeus) that initially were fed a standard diet. Each cohort then was divided into 2 groups, which received either standard chow or the Western diet. Food consumption and fecal quality were measured weekly. Body weight, waist circumference, and body-mass index were measured every 2 wk. CBC and clinical chemistry analyses were performed at baseline and 4 wk after the diet change. Plasma lipid concentrations, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, insulin, and fructosamine were measured at baseline and at 4, 8, and 12 wk after the diet change. Isoflavones were measured in the male monkeys at 6 wk after diet change, and lipid particle ...
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Papers by Jay Kaplan