Prenatal developmental toxicity studies on di-n-heptyl and di-n-octyl phthalates in Sprague-Dawley rats

This study evaluates the developmental toxicity of two dialkyl phthalate esters, di-n-heptyl phthalate (DHPP) and di-n-octyl (DnOP) phthalate, which have straight-alkyl side chains of seven and eight carbons, respectively. Sprague-Dawley rats were administered 0, 0.25, 0.50, or 1g/kg/day of DHPP or DnOP, by gavage, on gestation days 6-20. DHPP and DnOP had no adverse effect on maternal feed consumption and body weight gain, or on the incidence of post-implantation loss and fetal body weight. There was no increase in the incidence of fetal malformations or external and visceral variations, whatever treatment. A significant increase in rudimentary lumbar ribs was observed at all doses of DHPP and DnOP. The anogenital distance of the male fetuses was significantly decreased at the highest dose of DHPP. This parameter was not affected by DnOP. Thus, the lowest-observed-adverse-effect level (LOAEL) for developmental toxicity was 0.25 g/kg/day for DHPP and DnOP.     

The interactive effect of change in perceived stress and trait anxiety on vagal recovery from cognitive challenge

The present study tested the hypothesis that the change in state negative affect (measured as perceived stress) after cognitive challenge moderates the relationship of trait anxiety and anger to vagal recovery from that challenge.Cardiac vagal control (assessed using heart rate variability) and respiratory rate were measured in a sample of 905 participants from the Midlife in the United States Study. Cognitive challenges consisted of computerized mental arithmetic and Stroop color–word matching tasks. Multiple regression analyses controlling for the effects of the demographic, lifestyle, and medical factors influencing cardiac vagal control showed a significant moderating effect of change in perceived stress on the relationship of trait anxiety to vagal recovery from cognitive challenges (Beta = .253, p = .013). After adjustment for respiratory rate, this effect became marginally significant (Beta = .177, p = .037). In contrast, for the relationship of trait anger to vagal recovery, this effect was not significant either before (Beta = .141, p = .257) or after (Beta = .186, p = .072) adjusting for respiratory rate. Secondary analyses revealed that among the individuals with higher levels of trait anxiety, greater reductions in perceived stress were associated with greater increases in cardiac vagal control after the challenge. In contrast, among the individuals with lower levels of trait anxiety, changes in perceived stress had no impact on vagal recovery. Therefore, change in perceived stress moderates the relationship of trait anxiety, but not trait anger, to vagal recovery from cognitive challenge.     

In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin

Anthropogenic compounds with the capacity to interact with the steroid-binding site of sex hormone binding globulin (SHBG) pose health risks to humans and other vertebrates including fish. Building on studies of human SHBG, we have applied in silico drug discovery methods to identify potential binders for SHBG in zebrafish (Danio rerio) as a model aquatic organism. Computational methods, including; homology modeling, molecular dynamics simulations, virtual screening, and 3D QSAR analysis, successfully identified 6 non-steroidal substances from the ZINC chemical database that bind to zebrafish SHBG (zfSHBG) with low-micromolar to nanomolar affinities, as determined by a competitive ligand-binding assay. We also screened 80,000 commercial substances listed by the European Chemicals Bureau and Environment Canada, and 6 non-steroidal hits from this in silico screen were tested experimentally for zfSHBG binding. All 6 of these compounds displaced the [³H]5α-dihydrotestosterone used as labeled ligand in the zfSHBG screening assay when tested at a 33 μM concentration, and 3 of them (hexestrol, 4-tert-octylcatechol, and dihydrobenzo(a)pyren-7(8H)-one) bind to zfSHBG in the micromolar range. The study demonstrates the feasibility of large-scale in silico screening of anthropogenic compounds that may disrupt or highjack functionally important protein:ligand interactions. Such studies could increase the awareness of hazards posed by existing commercial chemicals at relatively low cost.     

Bilateral vagotomy or atropine pre-treatment reduces experimental diesel-soot induced lung inflammation

To investigate the role of the vagus nerve in acute inflammatory and cardiorespiratory responses to diesel particulate (DP) in the rat airway, we measured changes in respiration, blood pressure and neutrophils in lungs of urethane anesthetized Wistar rats 6-h post-instillation of DP (500 microg) and studied the effect of mid-cervical vagotomy or atropine (1 mg kg(-1)) pre-treatment. In conscious rats, we investigated DP, with and without atropine pre-treatment. DP increased neutrophil level in BAL (bronchoalveolar lavage) fluid from intact anesthetized rats to 2.5+/-0.7x10(6) cells (n=8), compared with saline instillation (0.3+/-0.1x10(6), n=7; P<0.05). Vagotomy reduced DP neutrophilia to 0.8+/-0.2x10(6) cells (n=8; P<0.05 vs. intact); atropine reduced DP-induced neutrophilia to 0.3+/-0.2x10(6) (n=4; P<0.05). In conscious rats, DP neutrophilia of 8.5+/-1.8x10(6), n=4, was reduced by pre-treatment with atropine to 2.2+/-1.2x10(6) cells, n=3. Hyperventilation occurred 6 h after DP in anesthetized rats with intact vagi, but not in bilaterally vagotomized or atropine pre-treated animals and was abolished by vagotomy (P<0.05, paired test). There were no significant differences in the other variables (mean blood pressure, heart rate and heart rate variability) measured before and 360 min after DP. In conclusion, DP activates a pro-inflammatory vago-vagal reflex which is reduced by atropine. Muscarinic ACh receptors in the rat lung are involved in DP-induced neutrophilia, and hence muscarinic antagonists may reduce airway and/or cardiovascular inflammation evoked by inhaled atmospheric DP in susceptible individuals.     

Study on developmental abnormalities in hypospadiac male rats induced by maternal exposure to di-n-butyl phthalate (DBP)

The objective of this study was to establish a hypospadiac rat model by maternal exposure to di-n-butyl phthalate (DBP) and to evaluate the developmental abnormalities of hypospadiac male rats. Timed-pregnant rats were given DBP by gastric intubation at doses of 0, 250, 500, 750 or 1000 mg/kg body weight (bw)/day from gestation day (GD) 14 to 18 to establish a hypospadiac rat model. The hypospadias was observed in the 500 and 750 mg/kg bw/day groups, the incidence of which was 6.8 and 41.3%, respectively. Transverse serial histological analysis of genitalia of hypospadiac male rats confirmed the malformation. With exposed dose increasing, the serum testosterone (T) levels of male rats inversely decreased, and in the same dosage group the serum T levels of hypospadiac rats were significantly lower than the levels of nonhypospadiac counterparts. The other reproductive lesions such as cryptorchidism and decreased ratio of anogenital distance/body weight (AGD/bw) were also observed. Autopsy analysis revealed the development of reproductive organs (prostate, testes, epididymis, pituitary gland) and nonreproductive organs (adrenal gland, liver, kidney, heart, spleen) of hypospadiac rats and nonhypospadiac counterparts. The results indicated that the reproductive system and developmental condition of hypospadiac male offspring were damaged severely by DBP.     

养血清脑颗粒联合缬沙坦氢氯噻嗪治疗老年原发性高血压的临床研究

目的 探讨养血清脑颗粒联合缬沙坦氢氯噻嗪片治疗老年原发性高血压的临床疗效。方法 选取2020年6月—2021年11月在保定市第一医院收治的82例老年原发性高血压患者为观察对象,根据随机数字表法将所有患者分为对照组和治疗组,每组各41例。对照组口服缬沙坦氢氯噻嗪片,1片/次,1次/d;治疗组在对照组治疗的基础上温水冲服养血清脑颗粒,1袋/次,3次/d。两组患者连续治疗3个月。观察两组的临床疗效,比较两组的血压指标、血流动力学指标、血清指标。结果 治疗后,治疗组患者的总有效率为95.12%,对照组的总有效率为80.49%,组间比较差异有统计学意义（P＜0.05）。治疗后,两组的24 h收缩压（24 h SBP）、24 h舒张压（24 h DBP）、24 h收缩压标准差（24 h SSD）、24 h舒张压标准差（24 h DSD）明显低于治疗前（P＜0.05）,且治疗组24 h SBP、24 h DBP、24 h SSD、24 h DSD低于对照组（P＜0.05）。治疗后,两组的体循环阻力（SVR）低于治疗前,心排血量（CO）、心脏指数（CI）高于治疗前（P＜0.05）;并且治疗组的SVR低于对照组,CO、CI高于对照组,差异有统计学意义（P＜0.05）。治疗后,两组的血清同型半胱氨酸（Hcy）、内皮素-1（ET-1）水平低于治疗前,一氧化氮（NO）水平高于治疗前（P＜0.05）;治疗组的Hcy、ET-1水平低于对照组,NO水平高于对照组（P＜0.05）。结论 养血清脑颗粒联合缬沙坦氢氯噻嗪片治疗老年原发性高血压的疗效确切,能有效控制血压,改善血流动力学指标和血管内皮功能,安全性良好。     

Use of the Adverse Outcome Pathway (AOP) framework to evaluate species concordance and human relevance of Dibutyl phthalate (DBP)-induced male reproductive toxicity

Dibutyl phthalate (DBP) is a phthalate ester used as a plasticizer, and solvent. Studies using rats consistently report that DBP exposure disrupts normal development of the male reproductive system in part via inhibition of androgen synthesis. However, studies using xenograft models report that in human fetal testis DBP exposure is unlikely to impair testosterone synthesis. These results question the validity of the rat model for assessment of male reproductive effects caused by DBP. The Adverse Outcome Pathway (AOP) framework was used to evaluate the available evidence for DBP-induced toxicity to the male reproductive system. Three relevant biological elements were identified: 1) fetal rats are more sensitive than other rodents and human fetal xenografts to DBP-induced anti-androgenic effects, 2) DBP-induced androgen-independent adverse outcomes are conserved amongst different mammalian models and human fetal testis xenografts, and 3) DBP-induced anti-androgenic effects are conserved in different mammalian species when exposure occurs during postnatal life stages.     

In Healthy Adults,Biological Activity of Vitamin D,as Assessed by Serum PTH,Is Largely Independent of DBP Concentrations

Vitamin D insufficiency, as measured by 25‐hydroxyvitamin D (25[OH]D) levels, has been associated with important health outcomes. The majority of vitamin D in circulation is bound to vitamin D–binding protein (DBP) and albumin, and recent genetic studies have demonstrated that serum DBP is a major determinant of 25(OH)D concentrations in adults. The impact of circulating DBP levels on vitamin D's biologic action, is unclear, but is of particular relevance to vitamin D epidemiology, because a lack of control for DBP levels could strongly influence the association of vitamin D with disease. Serum parathyroid hormone (PTH) levels can act as a biological readout of 25(OH)D activity. We therefore assessed the relationship between serum total and free 25(OH)D and PTH with and without adjusting for DBP, in 2073 subjects of European descent. Total 25(OH)D levels correlated positively (r = 0.19, p = 1.8 × 10^?17) with DBP, whereas the free 25(OH)D correlated negatively (r = ?0.14, p = 5.0 × 10^?12). Total and free 25(OH)D levels correlated negatively with PTH (r = ?0.29, p = 1.3 × 10^?39; r = ?0.26, p = 1.9 × 10^?33, respectively). Including age, body mass index (BMI), sex, estimated glomerular filtration rate, calcium, and season of blood draw as covariates, total 25(OH)D levels were significantly associated with log‐transformed PTH (lnPTH) levels (linear term: β = ?0.010, p < 0.0001, squared term: β = 0.00004, p < 0.0001) and this association was not changed by adjusting for DBP. These findings provide evidence that in a largely vitamin D–sufficient cohort, the biological effect of vitamin D on PTH levels is mainly independent of DBP concentration. Accordingly, this study may provide useful information for studies investigating the relationship between vitamin D, DBP, and disease. © 2014 American Society for Bone and Mineral Research.     

One hundred percent orange juice consumption is associated with better diet quality, improved nutrient adequacy, and no increased risk for overweight/obesity in children

The purpose of this study was to examine the association of 100% orange juice (OJ) consumption by children 2 to 18 years of age (n = 7250) participating in the 2003 to 2006 National Health and Nutrition Examination Survey with intakes of select nutrients, MyPyramid food groups, diet quality—measured by the Healthy Eating Index-2005, weight status, and associated risk factors. The National Cancer Institute method was used to estimate the usual intake of 100% OJ consumption, selected nutrients, and MyPyramid food groups. Percentages of the population below the Estimated Average Requirement were determined. Covariate adjusted logistic regression was used to determine if consumers had a lower odds ratio of being overweight or obese. Usual per capita intake of 100% OJ was 1.7 oz/d. Among consumers, the usual intake of 100% OJ for children (n = 2183; 26.2% of population) was 10.2 oz/d. Consumers had higher (P < .05) energy intakes than nonconsumers (9148 ± 113 vs 8625 ± 473 kJ). However, there were no differences in weight or body mass index in consumers and nonconsumers, and there was no significant difference in the risk of being overweight or obese between consumers and nonconsumers (odds ratio, 0.86; 95% confidence interval, 0.70-1.05). Compared with nonconsumers, consumers had a higher (P < .01) percentage (% ± SE) of the population meeting the Estimated Average Requirement for vitamin A (19.6 ± 2.0 vs 30.2 ± 1.4), vitamin C (0.0 ± 0.0 vs 29.2 ± 1.2), folate (1.3 ± 0.3 vs 5.1 ± 0.6), and magnesium (25.5 ± 2.0 vs 39.0 ± 11). The Healthy Eating Index-2005 was significantly (P < .01) higher in consumers (52.4 ± 0.4 vs 48.5 ± 0.3). Consumers also had higher intakes of total fruit, fruit juice, and whole fruit. Moderate consumption of 100% OJ should be encouraged in children as a component of a healthy diet.