Perfluorooctane sulfonate (PFOS) is a degradation product of sulfonyl-based fluorochemicals that are used extensively in industrial and household applications. Humans and wildlife are exposed to this class of compounds from several sources. Toxicity tests in rodents have raised concerns about potential developmental, reproductive, and systemic effects of PFOS. However, the effect of PFOS on the neuroendocrine system has not been investigated thus far. In this study, adult female rats were injected intraperitoneally with 0, 1, or 10 mg PFOS/kg body weight (BW) for 2 weeks. Food and water intake, BW, and estrous cycles were monitored daily. At the end of treatment, PFOS levels in tissues were measured by high-performance liquid chromatography (HPLC) interfaced with electrospray mass spectrometry. Changes in brain monoamines were measured by HPLC with electrochemical detection, and serum corticosterone and leptin were monitored using radioimmunoassay. Treatment with PFOS produced a dose-dependent accumulation of this chemical in various body tissues, including the brain. PFOS exposure decreased food intake and BW in a dose-dependent manner. Treatment with PFOS affected estrous cyclicity and increased serum corticosterone levels while decreasing serum leptin concentrations. PFOS treatment also increased norepinephrine concentrations in the paraventricular nucleus of the hypothalamus. These results indicate that exposure to PFOS can affect the neuroendocrine system in rats.

Obesity. 2006;14:1905-1913. Objective: Human adenovirus 36 (Ad-36) increases adiposity and reduces serum lipids in chicken, mouse, and nonhuman primate models, and it is linked to obesity in seroepidemiological studies in humans. Involvement of the central nervous system (CNS) or adipose tissue in the mechanism of Ad-36-induced adiposity is unknown. The effects of Ad-36 on adiposity and on the neuroendocrine system were investigated in a rat model. Research Methods and Procedures: Five-week-old male Wistar rats were inoculated intraperitoneally with Ad-36 or medium. Results: Despite similar food intakes, infected rats attained significantly greater body weight and fat pad weight by 30 weeks post-inoculation. Epididymal-inguinal, retroperitoneal, and visceral fat pad weights of the infected group were greater by 60%, 46%, and 86%, respectively (p Ͻ 0.00001). The fasting serum insulin level and homeostasis model assessment index indicated greater insulin sensitivity in the infected group. Visceral adipose tissue expression of glycerol 3-phosphate dehydrogenase, peroxisome proliferatoractivated receptor ␥, and CCAAT/enhancer-binding protein ␣ and ␤ was markedly increased in the infected animals compared with controls. Ad-36 decreased norepinephrine levels significantly in the paraventricular nucleus in infected vs. control rats (mean Ϯ standard error, 8.9 Ϯ 1.1 vs. 12.8 Ϯ 1.2 pg/g protein; p Ͻ 0.05). Ad-36 markedly decreased serum corticosterone in infected vs. control rats (mean Ϯ standard error, 97 Ϯ 41.0 vs. 221 Ϯ 111 ng/mL; p Ͻ 0.005). Discussion: The results suggest that the pro-adipogenic effect of Ad-36 may involve peripheral as well as central effects. The male Wistar rat is a good model for the elucidation of metabolic and molecular mechanisms of Ad-36-induced adiposity.

Prenatal testosterone excess in sheep leads to reproductive and metabolic disruptions that mimic those seen in women with polycystic ovary syndrome. Comparison of prenatal testosterone-treated sheep with prenatal dihydrotestosterone-treated sheep suggests facilitation of defects by androgenic as well as androgen-independent effects of testosterone. We hypothesized that the disruptive impact of prenatal testosterone on adult pathology may partially depend on its conversion to estrogen and consequent changes in maternal and fetal endocrine environments. Pregnant Suffolk sheep were administered either cottonseed oil (control) or testosterone propionate in cottonseed oil (100 mg, i.m. twice weekly), from Day 30 to Day 90 of gestation (term is ~147 d). Maternal (uterine) and fetal (umbilical) arterial samples were collected at Days 64-66, 87-90, and 139-140 (range; referred to as D65, D90, and D140, respectively) of gestation. Concentrations of gonadal and metabolic hormones, as well as differentiation factors, were measured using liquid chromatography/mass spectrometer, radioimmunoassay, or ELISA. Findings indicate that testosterone treatment produced maternal and fetal testosterone levels comparable to adult males and D65 control male fetuses, respectively. Testosterone treatment increased fetal estradiol and estrone levels during the treatment period in both sexes, supportive of placental aromatization of testosterone. These steroidal changes were followed by a reduction in maternal estradiol levels at term, a reduction in activin A availability, and induction of intrauterine growth restriction in D140 female fetuses. Overall, our findings provide the first direct evidence in support of the potential for both androgenic as well as estrogenic contribution in the development of adult reproductive and metabolic pathology in prenatal testosterone-treated sheep.

The roles of hypothalamic norepinephrine (NE) and dopamine (DA) in the regulation of LH and PRL are controversial. In the present studies, we used HPLC and push-pull perfusion to measure NE and DA releases in the medial preoptic area (MPA) of conscious, freely moving rats. Serum LH and PRL were determined in separate groups of rats with indwelling venous cannulas. In young (4- to 5-month-old) rats, concomitant with proestrous surges of serum LH and PRL, NE release in the MPA increased gradually to reach a peak at 1800 h, whereas DA release decreased gradually to its lowest level at 2000 h. Compared to the young animals, in middle-aged (8- to 10-month-old) animals, the proestrous surge of PRL was unaltered, but the LH surge was delayed and attenuated. The pattern of DA release in the middle-aged animals was also unaltered, but the peak in NE release was markedly attenuated, although the average NE release was increased compared to that in the young proestrous animals. In young diestrous rats and old (22- to 24-month-old), persistently diestrous rats, in which serum LH and PRL are known to be stable, both NE and DA releases were devoid of fluctuations. However, in the young diestrous animals, the average NE and DA releases were significantly increased compared to those in the young proestrous animals, whereas in the old, persistently diestrous animals, NE and DA releases were markedly reduced compared to those in the young diestrous animals. These data lead us to conclude that NE, through its stimulatory action, may be the primary regulator of LH release, and that it is the pattern, rather than the level, of NE release that appears to be critical in determining the pattern of LH release. DA, through its inhibitory action, appears to control PRL only and probably has no association with LH release. By tracing NE and DA activities from adulthood through middle-age to senescence, these studies revealed that the marked reductions in catecholamines in old age are preceded by a transitory increase in NE activity in middle-age, and that the cyclic increase in NE activity associated with the LH surge begins to diminish in middle age and disappears completely in old age.

TitleSudden acquired retinal degeneration syndrome (SARDS) -a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but responsive to blue light stimulation. In addition to blindness, the majority of affected dogs also show systemic abnormalities suggestive of hyperadrenocorticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a subclinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine and autoimmune mechanisms have been suggested. Therapies that target these disease pathways have been proposed to reverse or prevent further vision loss in SARDSaffected dogs, but these treatments are controversial. In November 2014, the American College of Veterinary Ophthalmologists' Vision for Animals Foundation organized and funded a Think Tank to review the current knowledge and recently proposed ideas about disease mechanisms and treatment of SARDS. These panel discussions resulted in recommendations for future research strategies toward a better understanding of pathogenesis, early diagnosis, and potential therapy for this condition.

King AJ, Olivier NB, Mohankumar PS, Lee JS, Padmanabhan V, Fink GD. Hypertension caused by prenatal testosterone excess in female sheep. Am J Physiol Endocrinol Metab 292: E1837-E1841, 2007. First published February 27, 2007; doi:10.1152/ajpendo.00668.2006.-Polycystic ovary syndrome (PCOS), a leading cause of infertility, affects ϳ10% of women of reproductive age. The etiology and pathophysiology of PCOS are poorly understood. PCOS is multifaceted and includes reproductive abnormalities and components of the metabolic syndrome such as insulin resistance, obesity, dyslipidemia, and hypertension. Exposure to excess testosterone (T) during the prenatal period may predispose individuals to PCOS phenotype. The goal of this study was to determine whether hypertension and dyslipidemia occur in a well-characterized model of PCOS produced by prenatal treatment of sheep with T. Radiotelemetry was used to measure blood pressure over a 24-h period in conscious, undisturbed animals. To normalize circulating estradiol levels across treatment, control (n ϭ 4) and prenatal T-treated (100 mg T propionate im twice weekly from days 30 to 90 of fetal life, n ϭ 4) 2-yr-old females were ovariectomized, instrumented with a radiotelemetry transmitter, and clamped with early follicular phase levels of estrogen using an implant. Six days later, a 24-h recording period commenced. Prenatal T-treated sheep were hypertensive compared with control sheep, and heart rate tended to be higher. T-treated sheep had hyperglycemia, insulin resistance, hypernatremia, and hyperchloremia, and both total and LDL cholesterol tended to be higher. Plasma aldosterone and epinephrine were significantly lower in T-treated sheep, whereas norepinephrine was unchanged. This first-ever use of radiotelemetric blood pressure recordings in sheep demonstrates that mild hypertension, a risk factor reported in some women with PCOS, is also a feature of the sheep model of PCOS produced by prenatal T treatment. intrauterine programming; polycystic ovary syndrome; dyslipidemia; hyperglycemia; hypernatremia A SUBOPTIMAL INTRAUTERINE ENVIRONMENT, resulting in impaired fetal growth, is associated with a higher incidence of cardiovascular, metabolic, and reproductive disorders in adult life (26,34). An abnormal intrauterine hormonal milieu can clearly influence fetal growth and development and has been identified as one factor known to cause intrauterine programming (25,26). For instance, excessive prenatal exposure to glucocorticoids causes hypertension, insulin resistance, and other metabolic abnormalities in numerous animal models, including sheep (10,11,27,46). The sex steroids are well-established intrauterine programming agents in many species, including in sheep (36). Exposure to excess testosterone (T) during the prenatal period causes phenotypic masculinization, intrauterine growth retardation (7,32,33,42), reproductive disruptions, and insulin resistance (39) and recreates the polycystic ovary syndrome (PCOS) phenotype in female sheep (36).PCOS, which affects ϳ10% of...

Objective: Consumption of a high-fat (HF) diet is a contributing factor for the development of obesity. HF diet per se acts as a stressor, stimulating hypothalamo-pituitary-adrenal (HPA) axis activity resulting in elevated glucocorticoid levels; however, the mechanism behind this activation is unclear. We hypothesized that consumption of an HF diet activates HPA axis by increasing norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, leading to elevation in corticotrophin-releasing hormone (CRH) concentration in the median eminence (ME) resulting in elevated serum corticosterone (CORT). Subjects: To test this hypothesis, diet-induced obese (DIO) and diet-resistant (DR) rats were exposed to either chow or HF diet for 6 weeks. Measurements: At the end of 6 weeks, NE in the PVN was measured using HPLC, CRH in the ME, and CORT and leptin levels in the serum were measured using RIA and ELISA, respectively. The gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in NE synthesis, and leptin receptor in brainstem noradrenergic nuclei were also measured. Results: HF diet increased PVN NE in both DIO and DR rats (Po0.05). However, this was accompanied by increases in CRH and CORT secretion only in DR animals, but not in DIO rats. Leptin receptor mRNA levels in the brainstem noradrenergic areas were not affected in both DIO and DR rats. However, HF diet increased TH mRNA levels only in DIO rats. Conclusion: Significant differences occur in all the arms of HPA axis function between DIO and DR rats. Further studies are needed to determine whether this could be a causative factor or a consequence to obesity.

BACKGROUND Incidence of ovulatory disorders is common in obese animal models. The mechanism behind this effect is not clear. We hypothesized that high fat (HF) diet induces alterations in neuroendocrine mechanisms resulting in anovulation in diet-induced obese (DIO) animals. METHODS Adult female DIO and diet-resistant (DR) rats were fed either chow or HF diet (45% calories from fat) for 6 weeks. Oestrous cyclicity and body weight were monitored regularly. At the end of treatment, rats were implanted with a jugular catheter to monitor luteinising hormone (LH) levels on the day of prooestrous. Rats were sacrificed on the following prooestrous, their brains and ovaries were collected. Plasma from trunk blood was analyzed for oestradiol and leptin concentrations. Ovaries were fixed and sectioned for histological analysis. Brains were removed, frozen and sectioned and norepinephrine (NE) concentrations in discrete hypothalamic areas were measured using HPLC-EC. RESULTS HF diet affected oestrous cyclicity in both DIO and DR rats with the effect being more pronounced in DIO animals. HF diet increased leptin levels in both DIO and DR rats. Oestradiol levels were low in the DIO-HF group. NE levels in the hypothalamus were unaffected by HF diet or genotype. A normal LH surge was observed in DR-Chow rats and LH levels were low in the rest of the groups. CONCLUSION DIO rats have an inherently reduced reproductive capacity and exposure to a HF diet decreases it further. A reduction in oestradiol and LH surge levels could contribute to this effect, however the underlying mechanisms need to be studied further.