The Case for BPA as an Obesogen: Contributors to the Controversy

Since the inception of the term endocrine disruptor, the idea that the environment is an important determinant of phenotype has motivated researchers to explore the effect of low dose exposure to BPA during organogenesis. The syndrome observed was complex, affecting various endpoints such as reproduction and reproductive tissues, behavior, mammary gland development and carcinogenesis, glucose homeostasis, and obesity. This constellation of impacted endpoints suggests the possibility of complex interactions among the multiple effects of early BPA exposure. One key finding of our rodent studies was alterations of energy and amino-acid metabolism that were detected soon after birth and continued to be present at all time points examined through 6 months of age. The classical manifestations of obesity and associated elements of metabolic disease took a longer time to become apparent. Here we examine the validity of the often-mentioned lack of reproducibility of obesogenic effects of BPA, starting from the known environmental causes of variation, which are diverse and range from the theoretical like the individuation process and the non-monotonicity of the dose-response curve, to the very pragmatic like housing, feed, and time and route of exposure. We then explore environmental conditions that may hinder reproducibility and discuss the effect of confounding factors such as BPA-induced hyperactivity. In spite of all the potential sources of variation, we find that some obesogenic or metabolic effects of BPA are reproducibly observed when study conditions are analogous. We recommend that study authors describe details of their study conditions including the environment, husbandry, and feed. Finally, we show that when experimental conditions are strictly maintained, reproducibility, and stability of the obese phenotype is consistently observed

Perinatal Bisphenol A Exposure Increases Estrogen Sensitivity of the Mammary Gland in Diverse Mouse Strains

BACKGROUND: Studies of low-dose effects of xenoestrogens have yielded conflicting results that may be attributed to differences in estrogen sensitivity between the rodent strains examined. Perinatal exposure of CD-1 mice to low doses of the xenoestrogen bisphenol A (BPA) alters peripubertal mammary gland development. Future studies to assess the role of estrogen receptors as mediators of BPA action require estrogen receptor knock-out mice that were generated on a C57Bl6 background. The sensitivity of the C57Bl6 strain to estradiol and BPA is unknown. OBJECTIVES: In the present study we examined whether the mammary glands of CD-1 and C57Bl6 mice exhibited similar responses to 17β-estradiol (E(2)) and whether perinatal exposure to BPA equally enhanced sensitivity of the mammary glands to E(2) at puberty. METHODS: Immature mice were ovariectomized and treated for 10 days with one of eight doses of E(2). Morphological mammary gland parameters were examined to identify doses producing half-maximal effects. Mice were exposed perinatally to 0 or 250 ng BPA/kg body weight (bw)/day from gestational day 8 until postnatal day (PND) 2. On PND25, female offspring were ovariectomized and given an estrogen challenge of 0, 0.5, or 1 μg E(2)/kg bw/day for 10 days. Morphometric parameters of the mammary gland were compared between strains. RESULTS: Both strains exhibited similar responses to E(2). Perinatal BPA exposure altered responses to E(2) at puberty for several parameters in both strains, although the effect in CD-1 was slightly more pronounced. CONCLUSION: Both mouse strains provide adequate models for the study of perinatal exposure to xenoestrogens

In Vivo Effects of Bisphenol A in Laboratory Rodent Studies

Concern is mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical used in synthesis of plastics. We have reviewed the growing literature on effects of low doses of BPA, below 50 mg/kg/day, in laboratory exposures with mammalian model organisms. Many, but not all, effects of BPA are similar to effects seen in response to the model estrogens diethylstilbestrol and ethinylestradiol. For most effects, the potency of BPA is approximately 10 to 1,000-fold less than that of diethylstilbestrol or ethinylestradiol. Based on our review of the literature, a consensus was reached regarding our level of confidence that particular outcomes occur in response to low-dose BPA exposure. We are confident that adult exposure to BPA affects the male reproductive tract, and that long-lasting, organizational effects in response to developmental exposure to BPA occur in the brain, the male reproductive system, and metabolic processes. We consider it likely, but requiring further confirmation, that adult exposure to BPA affects the brain, the female reproductive system, and the immune system, and that developmental effects occur in the female reproductive system

An Update on Cancer Cluster Activities at the Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) continues to be aware of the need for response to public concern as well as to state and local agency concern about cancer clusters. In 1990 the CDC published the “Guidelines for Investigating Clusters of Health Events,” in which a four-stage process was presented. This document has provided a framework that most state health departments have adopted, with modifications pertaining to their specific situations, available resources, and philosophy concerning disease clusters. The purpose of this present article is not to revise the CDC guidelines; they retain their original usefulness and validity. However, in the past 15 years, multiple cluster studies as well as scientific and technologic developments have affected cluster science and response (improvements in cancer registries, a federal initiative in environmental public health tracking, refinement of biomarker technology, cluster identification using geographic information systems software, and the emergence of the Internet). Thus, we offer an addendum for use with the original document. Currently, to address both the needs of state health departments as well as public concern, the CDC now a) provides a centralized, coordinated response system for cancer cluster inquiries, b) supports an electronic cancer cluster listserver, c) maintains an informative web page, and d) provides support to states, ranging from laboratory analysis to epidemiologic assistance and expertise. Response to cancer clusters is appropriate public health action, and the CDC will continue to provide assistance, facilitate communication among states, and foster the development of new approaches in cluster science

Perinatal Exposure to Environmentally Relevant Levels of Bisphenol A Decreases Fertility and Fecundity in CD-1 Mice

Bac k g r o u n d: Perinatal exposure to low-doses of bisphenol A (BPA) results in alterations in the ovary, uterus, and mammary glands and in a sexually dimorphic region of the brain known to be important for estrous cyclicity. Objectives: We aimed to determine whether perinatal exposure to environmentally relevant doses of BPA alters reproductive capacity. Met h o d s: Female CD-1 mice that were exposed to BPA at 0, 25 ng, 250 ng, or 25 µg/kg body weight (BW)/day or diethylstilbestrol (DES) at 10 ng/kg BW/day (positive control) from gestational day 8 through day 16 of lactation were continuously housed with proven breeder males for 32 weeks starting at 2 months of age. At each delivery, pups born to these mating pairs were removed. The cumulative number of pups, number of deliveries, and litter size were recorded. The purity of the BPA used in this and our previous studies was assessed using HPLC, mass spectrometry, and nuclear magnetic resonance. Res u l t s: The forced breeding experiment revealed a decrease in the cumulative number of pups, observed as a nonmonotonic dose–response effect, and a decline in fertility and fecundity over time in female mice exposed perinatally to BPA. The BPA was 97 % pure, with no evidence of contaminatio

Measurement of Charged Pion Production Yields off the NuMI Target

The fixed-target MIPP experiment, Fermilab E907, was designed to measure the production of hadrons from the collisions of hadrons of momenta ranging from 5 to 120 GeV/c on a variety of nuclei. These data will generally improve the simulation of particle detectors and predictions of particle beam fluxes at accelerators. The spectrometer momentum resolution is between 3 and 4%, and particle identification is performed for particles ranging between 0.3 and 80 GeV/c using $dE/dx$, time-of-flight and Cherenkov radiation measurements. MIPP collected $1.42 \times10^6$ events of 120 GeV Main Injector protons striking a target used in the NuMI facility at Fermilab. The data have been analyzed and we present here charged pion yields per proton-on-target determined in bins of longitudinal and transverse momentum between 0.5 and 80 GeV/c, with combined statistical and systematic relative uncertainties between 5 and 10%.Comment: 15 pages, 13 figure

DHA supplementation during pregnancy does not reduce BMI or body fat mass in children: follow-up of the DHA to Optimize Mother Infant Outcome randomized controlled trial

First published March 30, 2016The omega-3 (n-3) long-chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) has proven effective at reducing fat storage in animal studies. However, a systematic review of human trials showed a lack of quality data to support or refute this hypothesis.We sought to determine whether maternal DHA supplementation during the second half of pregnancy results in a lower body mass index (BMI) and percentage of body fat in children.We conducted a follow-up at 3 and 5 y of age of children who were born to mothers enrolled in the DOMInO (DHA to Optimize Mother Infant Outcome) double-blind, randomized controlled trial, in which women with a singleton pregnancy were provided with DHA-rich fish-oil capsules (800 mg DHA/d) or vegetable-oil capsules (control group) in the second half of pregnancy. Primary outcomes were the BMIzscore and percentage of body fat at 3 and 5 y of age. Potential interactions between prenatal DHA and the peroxisome proliferator-activated receptor-γ (PPARγ) genotype as a measure of the genetic predisposition to obesity were investigated.A total of 1614 children were eligible for the follow-up. Parent or caregiver consent was obtained for 1531 children (95%), and these children were included in the analysis. BMIzscores and percentages of body fat of children in the DHA group did not differ from those of children in the control group at either 3 y of age [BMIzscore adjusted mean difference: 0.03 (95% CI: -0.07, 0.13;P= 0.61); percentage of body fat adjusted mean difference: -0.26 (95% CI: -0.99, 0.46;P= 0.47)] or 5 y of age [BMIzscore adjusted mean difference: 0.02 (95% CI: -0.08, 0.12;P= 0.66); percentage of body fat adjusted mean difference: 0.11 (95% CI: -0.60, 0.82;P= 0.75)]. No treatment effects were modified by thePPARγgenotype of the child.Independent of a genetic predisposition to obesity, maternal intake of DHA-rich fish oil during the second half of pregnancy does not affect the growth or body composition of children at 3 or 5 y of age. This trial was registered atwww.anzctr.org.auas ACTRN1260500056906 and ACTRN12611001127998.Beverly S Muhlhausler, Lisa N Yelland, Robyn McDermott, Linda Tapsell, Andrew McPhee, Robert A Gibson, and Maria Makride

Fall, Recovery and Characterization of the Novato L6 Chondrite Breccia

The Novato L6 chondrite fragmental breccia fell in California on 17 October 2012, and was recovered after the Cameras for Allsky Meteor Surveillance (CAMS) project determined the meteor's trajectory between 95 and 45 km altitude. The final fragmentation at 33 1 km altitude was exceptionally well documented by digital photographs. The first sample was recovered before rain hit the area. First results from a consortium study of the meteorite's characterization, cosmogenic and radiogenic nuclides, origin and conditions of the fall are presented. Some meteorites did not retain fusion crust and show evidence of spallation. Before entry, the meteoroid was 35+/-5 cm in diameter (mass 80+/-35 kg) with a cosmic ray exposure age of 9+/-1 Ma, if it had a one-stage exposure history. However, based on the cosmogenic nuclide inventory, a two-stage exposure history is more likely, with lower shielding in the last few Ma. Thermoluminescence data suggest a collision event within the last approx. 0.1 Ma. Novato likely belonged to the class of shocked L chondrites that have a common shock age of 470 Ma, based on the U,Th-He age of 460+/-220 Ma. The measured orbits of Novato, Jesenice and Innisfree are consistent with a proposed origin of these shocked L chondrites in the Gefion asteroid family, but leave open the possibility that they came to us directly from the 5:2 mean motion resonance with Jupiter. Novato experienced a stronger compaction than did other L6 chondrites of shock-stage S4. Despite this, a freshly broken surface shows a wide range of organic compounds

The landscape of somatic copy-number alteration across human cancers

available in PMC 2010 August 18.A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109038))National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109467)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA085859)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA 098101)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, K08CA122833

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead