Psychosocial Stress Exposure Disrupts Mammary Gland Development.

Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8-25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.

Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice.

The cytochrome P450 (CYP) 1 family is active toward numerous environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs). Utilizing a mouse model, null for Cyp1b1 and expressing human CYP1B1, we tested the hypothesis that hCYP1B1 is important for dibenzo[def,p]chrysene (DBC) transplacental carcinogenesis. Wild-type mCyp1b1, transgenic hCYP1B1 (mCyp1b1 null background), and mCyp1b1 null mice were assessed. Each litter had an equal number of siblings with Ahrb-1/d and Ahrd/d alleles. Pregnant mice were dosed (gavage) on gestation day 17 with 6.5 or 12 mg/kg of DBC or corn oil. At 10 months of age, mortality, general health, lymphoid disease and lung tumor incidence, and multiplicity were assessed. hCYP1B1 genotype did not impact lung tumor multiplicity, but tended to enhance incidence compared to Cyp1b1 wild-type mice (P = 0.07). As with Cyp1b1 in wild-type mice, constitutive hCYP1B1 protein is non-detectable in liver but was induced with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Wild-type mice were 59% more likely to succumb to T-cell Acute Lymphoblastic Leukemia (T-ALL). Unlike an earlier examination of the Ahr genotype in this model (Yu et al., Cancer Res, 2006;66:755-762), but in agreement with a more recent study (Shorey et al., Toxicol Appl Pharmacol, 2013;270:60-69), this genotype was not associated with lung tumor incidence, multiplicity, or mortality. Sex was not significant with respect to lung tumor incidence or mortality but males exhibited significantly greater multiplicity. Lung tumor incidence was greater in mCyp1b1 nulls compared to wild-type mice. To our knowledge, this is the first application of a humanized mouse model in transplacental carcinogenesis. © 2016 Wiley Periodicals, Inc.

Role of gut microbiota in type 2 diabetes pathophysiology.

A substantial body of literature has provided evidence for the role of gut microbiota in metabolic diseases including type 2 diabetes. However, reports vary regarding the association of particular taxonomic groups with disease. In this systematic review, we focused on the potential role of different bacterial taxa affecting diabetes. We have summarized evidence from 42 human studies reporting microbial associations with disease, and have identified supporting preclinical studies or clinical trials using treatments with probiotics. Among the commonly reported findings, the genera of Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia and Roseburia were negatively associated with T2D, while the genera of Ruminococcus, Fusobacterium, and Blautia were positively associated with T2D. We also discussed potential molecular mechanisms of microbiota effects in the onset and progression of T2D.

Prevalence of bacterial vaginosis and Candida among postmenopausal women in the United States.

OBJECTIVES: To describe the prevalence of bacterial vaginosis (BV) and Candida among community-dwelling postmenopausal women in the United States and determine their change with age, using estimates based on Waves 1 and 2 of the National Social Life, Health and Aging Project (NSHAP). METHOD: Self-administered vaginal swabs were collected in-home from women aged 57-85 (n = 1,016) in Wave 1 and again 5 years later in Wave 2 (n = 883). Gram-stained specimens were evaluated for BV using the Nugent score as well as presence of Candida. RESULTS: BV was prevalent in 23% and 38% of postmenopausal women in Waves 1 and 2 and increased with age. Women initially categorized with BV in Wave 1 were more than 10 times as likely to be categorized with BV in Wave 2, relative risk ratio (RRR) = 10.5; 95% confidence interval (CI) (4.45-24.7); p < .001, whereas women initially categorized as intermediate in Wave 1 were five times more likely to have a BV categorization, RRR = 5.0; 95% CI (2.56-9.75); p < .001. Although the presence of Candida was similar in both waves (6% and 5%), its relationship with age only became evident in Wave 2, with odds of detecting Candida decreasing by 7% with each year of age, OR = 0.93, 95% CI (0.88, 0.98); p = .010. DISCUSSION: In Wave 2, the prevalence of BV was higher and increased with age while the prevalence of Candida was low and declined with age. A 5-year age increase contributed to the prevalence change across waves. Methods refinements in Wave 2 improved the detection of BV and Candida and clarified their relationship with age.

Social peptides: measuring urinary oxytocin and vasopressin in a home field study of older adults at risk for dehydration.

OBJECTIVES: We present the novel urine collection method used during in-home interviews of a large population representative of older adults in the United States (aged 62-91, the National Social Life, Health and Aging Project). We also present a novel assay method for accurately measuring urinary peptides oxytocin (OT) and vasopressin (AVP), hormones that regulate social behaviors, stress, and kidney function. METHOD: Respondents in a randomized substudy (N = 1,882) used airtight containers to provide urine specimens that were aliquoted, stored under frozen refrigerant packs and mailed overnight for frozen storage (-80 °C). Assays for OT, AVP, and creatinine, including freeze-thaw cycles, were refined and validated. Weighted values estimated levels in the older U.S. population. RESULTS: Older adults had lower OT, but higher AVP, without the marked gender differences seen in young adults. Mild dehydration, indicated by creatinine, specific gravity, acidity, and AVP, produced concentrated urine that interfered with the OT assay, yielding falsely high values (18% of OT). Creatinine levels (≥ 1.4 mg/ml) identified such specimens that were diluted to solve the problem. In contrast, the standard AVP assay was unaffected (97% interpretable) and urine acidity predicted specimens with low OT concentrations. OT and AVP assays tolerated 2 freeze-thaw cycles, making this protocol useful in a variety of field conditions. DISCUSSION: These novel protocols yielded interpretable urinary OT and AVP values, with sufficient variation for analyzing their social and physiological associations. The problem of mild dehydration is also likely common in animal field studies, which may also benefit from these collection and assay protocols.

Survey field methods for expanded biospecimen and biomeasure collection in NSHAP Wave 2.

OBJECTIVES: The National Social Life, Health, and Aging Project is a nationally representative, longitudinal survey of older adults. A main component is the collection of biomeasures to objectively assess physiological status relevant to psychosocial variables, aging conditions, and disease. Wave 2 added novel biomeasures, refined those collected in Wave 1, and provides a reference for the collection protocols and strategy common to the biomeasures. The effects of aging, gender, and their interaction are presented in the specific biomeasure papers included in this Special Issue. METHOD: A transdisciplinary working group expanded the biomeasures collected to include physiological, genetic, anthropometric, functional, neuropsychological, and sensory measures, yielding 37 more than in Wave 1. All were designed for collection in respondents' homes by nonmedically trained field interviewers. RESULTS: Both repeated and novel biomeasures were successful. Those in Wave 1 were refined to improve quality, and ensure consistency for longitudinal analysis. Four new biospecimens yielded 27 novel measures. During the interview, 19 biomeasures were recorded covering anthropometric, functional, neuropsychological, and sensory measures and actigraphy provided data on activity and sleep. DISCUSSION: Improved field methods included in-home collection, temperature control, establishment of a central survey biomeasure laboratory, and shipping, all of which were crucial for successful collection by the field interviewers and accurate laboratory assay of the biomeasures (92.1% average co-operation rate and 97.3% average assay success rate). Developed for home interviews, these biomeasures are readily applicable to other surveys.