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Concept: Endocrinology

235

BACKGROUND: Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours. METHODS: 1006 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case–control design, exposure effects were estimated using conditional logistic regression. RESULTS: Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5). CONCLUSIONS: These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.

Concepts: Cancer, Breast cancer, Oncology, Estrogen, Endocrinology, Estrogen receptor, Endocrine system, Endocrine disruptor

152

Phenotypic differences among species may evolve through genetic accommodation, but mechanisms accounting for this process are poorly understood. Here we compare hormonal variation underlying differences in the timing of metamorphosis among three spadefoot toads with different larval periods and responsiveness to pond drying. We find that, in response to pond drying, Pelobates cultripes and Spea multiplicata accelerate metamorphosis, increase standard metabolic rate (SMR), and elevate whole-body content of thyroid hormone (the primary morphogen controlling metamorphosis) and corticosterone (a stress hormone acting synergistically with thyroid hormone to accelerate metamorphosis). In contrast, Scaphiopus couchii has the shortest larval period, highest whole-body thyroid hormone and corticosterone content, and highest SMR, and these trait values are least affected by pond drying among the three species. Our findings support that the atypically rapid and canalized development of S. couchii evolved by genetic accommodation of endocrine pathways controlling metamorphosis, showing how phenotypic plasticity within species may evolve into trait variation among species.

Concepts: Evolution, Metabolism, Endocrinology, Thyroid, Thyroid hormone, Adrenal cortex, Amphibian, Toads

105

Esteban Gonzalez Burchard and colleagues explore how making medical research more diverse would aid not only social justice but scientific quality and clinical effectiveness, too.

Concepts: Endocrinology, Medical research, Orphan drug

95

Young researchers are crucially important for basic science as they make unexpected, fundamental discoveries. Since 1982, we find a steady drop in the number of grant-eligible basic-science faculty [principal investigators (PIs)] younger than 46. This fall occurred over a 32-y period when inflation-corrected congressional funds for NIH almost tripled. During this time, the PI success ratio (fraction of basic-science PIs who are R01 grantees) dropped for younger PIs (below 46) and increased for older PIs (above 55). This age-related bias seems to have caused the steady drop in the number of young basic-science PIs and could reduce future US discoveries in fundamental biomedical science. The NIH recognized this bias in its 2008 early-stage investigator (ESI) policy to fund young PIs at higher rates. We show this policy is working and recommend that it be enhanced by using better data. Together with the National Institute of General Medical Sciences (NIGMS) Maximizing Investigators' Research Award (MIRA) program to reward senior PIs with research time in exchange for less funding, this may reverse a decades-long trend of more money going to older PIs. To prepare young scientists for increased demand, additional resources should be devoted to transitional postdoctoral fellowships already offered by NIH.

Concepts: Scientific method, Endocrinology, Science, Research, Medical research, Funding, Biomedical scientist, National Institute of General Medical Sciences

61

Persistent exposure to man-made endocrine disrupting chemicals during fetal endocrine development may lead to disruption of metabolic homeostasis contributing to childhood obesity. Limited cellular platforms exist to test endocrine disrupting chemical-induced developmental abnormalities in human endocrine tissues. Here we use an human-induced pluripotent stem cell-based platform to demonstrate adverse impacts of obesogenic endocrine disrupting chemicals in the developing endocrine system. We delineate the effects upon physiological low-dose exposure to ubiquitous endocrine disrupting chemicals including, perfluoro-octanoic acid, tributyltin, and butylhydroxytoluene, in endocrine-active human-induced pluripotent stem cell-derived foregut epithelial cells and hypothalamic neurons. Endocrine disrupting chemicals induce endoplasmic reticulum stress, perturb NF-κB, and p53 signaling, and diminish mitochondrial respiratory gene expression, spare respiratory capacity, and ATP levels. As a result, normal production and secretion of appetite control hormones, PYY, α-MSH, and CART, are hampered. Blocking NF-κB rescues endocrine disrupting chemical-induced aberrant mitochondrial phenotypes and endocrine dysregulation, but not ER-stress and p53-phosphorylation changes.Harmful chemicals that disrupt the endocrine system and hormone regulation have been associated with obesity. Here the authors apply a human pluripotent stem cell-based platform to study the effects of such compounds on developing gut endocrine and neuroendocrine systems.

Concepts: Cell, Metabolism, Developmental biology, Endoplasmic reticulum, Obesity, Endocrinology, Endocrine system, Endocrine disruptor

58

Osteocalcin (OCN) is an osteoblast-derived hormone that increases energy expenditure, insulin sensitivity, insulin secretion, and glucose tolerance. The cDNA sequence of OCN predicts that, like many other peptide hormones, OCN is first synthesized as a prohormone (pro-OCN). The importance of pro-OCN maturation in regulating OCN and the identity of the endopeptidase responsible for pro-OCN cleavage in osteoblasts are still unknown. Here, we show that the proprotein convertase furin is responsible for pro-OCN maturation in vitro and in vivo. Using pharmacological and genetic experiments, we also determined that furin-mediated pro-OCN cleavage occurred independently of its γ-carboxylation, a posttranslational modification that is known to hamper OCN endocrine action. However, because pro-OCN is not efficiently decarboxylated and activated during bone resorption, inactivation of furin in osteoblasts in mice resulted in decreased circulating levels of undercarboxylated OCN, impaired glucose tolerance, and reduced energy expenditure. Furthermore, we show that Furin deletion in osteoblasts reduced appetite, a function not modulated by OCN, thus suggesting that osteoblasts may secrete additional hormones that regulate different aspects of energy metabolism. Accordingly, the metabolic defects of the mice lacking furin in osteoblasts became more apparent under pair-feeding conditions. These findings identify furin as an important regulator of bone endocrine function.

Concepts: Bone, Metabolism, Adenosine triphosphate, Insulin, Diabetes mellitus, Hormone, Endocrinology, Carbohydrate

58

Phytoestrogens are plant-derived dietary compounds with structural similarity to 17-β-estradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)estrogenic effects by binding to the estrogen receptors. The aim of the present review is to present a state-of-the-art overview of the the potential health effects of dietary phytoestrogens. Various beneficial health effects have been ascribed to phytoestrogens, such as a lowered risk on menopausal symptoms like hot flushes and osteoporosis, lowered risks on cardiovascular disease, obesity, metabolic syndrome and type 2 diabetes, brain function disorders, breast cancer, prostate cancer, bowel cancer and other cancers. In contrast to these beneficial health claims, the (anti)estrogenic properties of phytoestrogens have also raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects. The literature overview presented in this paper illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. Furthermore, the currently available data are not sufficient to support a more refined (semi) quantitative risk-benefit analysis. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made.

Concepts: Cancer, Breast cancer, Metastasis, Nutrition, Obesity, Menopause, Estrogen, Endocrinology

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DESCRIPTION: Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation statement on hormone therapy for the prevention of chronic conditions in postmenopausal women. METHODS: The USPSTF commissioned a review of the literature to update evidence about the benefits and harms of using menopausal hormone therapy to prevent chronic conditions, as well as whether the benefits and harms of hormone therapy differ by population subgroups defined by age; the presence of comorbid medical conditions; and the type, dose, and method of hormonal delivery. POPULATION: This recommendation applies to postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to women who are considering hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to women younger than 50 years who have had surgical menopause. RECOMMENDATION: The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women. (Grade D recommendation)The USPSTF recommends against the use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy. (Grade D recommendation).

Concepts: Osteoporosis, Hormone replacement therapy, Medicine, Hormone, Menopause, Estrogen, Endocrinology, Luteinizing hormone

34

The prospective association between cardiorespiratory fitness (CRF) measured in young adulthood and middle age on development of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance, or diabetes by middle age remains unknown. We hypothesised that higher fitness levels would be associated with reduced risk for developing incident prediabetes/diabetes by middle age.

Concepts: Nutrition, Insulin, Middle Ages, Endocrinology, Glucose tolerance test, Impaired fasting glycaemia, Impaired glucose tolerance, Young adult

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Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We show that both A6 and an anilinopyrimidine, cyprodinyl, decrease larval survival and affect central neurons at micromolar concentrations. Focusing on a superficial and easily observable sensory system, the lateral line system, we found that defects in axonal and sensory cell regeneration can be observed at much lower doses, in the nanomolar range. We also show that A6 accumulates preferentially in lateral line neurons and hair cells. We examined whether A6 affects the expression of putative target genes, and found that genes involved in apoptosis/cell proliferation are down-regulated, as well as genes reflecting estrogen receptor activation, consistent with previous reports that anilinopyrimidines act as endocrine disruptors. On the other hand, canonical targets of endocrine signaling are not affected, suggesting that the neurotoxic effect of A6 may be due to the binding of this compound to a recently identified, neuron-specific estrogen receptor.

Concepts: Effect, Endocrinology, Affect, Sense, Pesticide, Endocrine system, Endocrine disruptor, Neurotoxicity