Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice.

Maternal behavior in mammals is the result of a complex interaction between the lactating dam and her developing offspring. Slight perturbations of any of the components of the mother-infant interaction may result in alterations of the behavior of the mother and/or of the offspring. We studied the effects of exposure of female CD-1 mice to the estrogenic chemical bisphenol A (BPA) during fetal life and/or in adulthood during the last part of pregnancy on subsequent maternal behavior. Pregnant females were fed daily doses of corn oil (controls) or 10 microg/kg body weight BPA during gestation days 14-18. As adults, the prenatally treated female offspring were time-mated and again fed either corn oil (controls) or the same doses of BPA on gestation days 14-18, resulting in four treatment groups: controls, prenatal BPA exposure, adult BPA exposure, and both prenatal and adult BPA exposure. Maternal behavior was then observed on postnatal days 2-15 and reflex responses were examined in the offspring. Dams exposed to BPA either as fetuses or in adulthood spent less time nursing their pups and more time out of the nest compared with the control group. Females exposed to BPA both as fetuses and in adulthood did not significantly differ from controls. No alterations in postnatal reflex development were observed in the offspring of the females exposed to BPA. The changes seen in maternal behavior may be the result of a direct effect of BPA on the neuroendocrine substrates underlying the initiation of maternal behavior

A Clash of Old and New Scientific Concepts in Toxicity, with Important Implications for Public Health

Background A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that “the dose makes the poison”: higher doses will cause greater effects. Objectives We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments. Discussion Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants. Conclusions We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds

Benefits of soy-based feeds for fetal estrogen levels and obesity in adulthood

Abstract only availableWe examined the effect of maternal exposure to naturally occurring estrogenic chemicals in diets on circulating levels of estradiol in mouse fetuses. An animal's specific response to estrogen can vary according to the time of exposure. The time when the fetus is sensitive to permanent “programming” effects of estrogen is called a “critical period” in development of organ systems. An important factor in the regulation of estrogen in the fetus is the composition of the mother's diet. Our hypothesis was that if a diet that was fed to pregnant mice during the fetal critical period contained estrogenic chemicals, these chemicals would “estrogenize” the fetus. In contrast to this prediction, a casein-based diet with virtually no estrogenic chemicals led to significantly higher levels of endogenous estradiol relative to a soy-based diet with very high levels of estrogenic chemicals. In a follow-up experiment we compared a soy-based diet containing estrogenic chemicals with a soy-based diet from which these estrogenic chemicals were extracted. The complete soy diet resulted in estrodiol levels of 60 pg/ml in fetal serum, while the extracted soy diet dramatically increased serum estradiol by over 50%. This finding shows that the naturally occurring estrogens in soy (phytoestrogens) fed to pregnant mice reduce endogenous estradiol levels in the fetuses. This is important since elevated levels of estradiol during fetal life "program" certain characteristics into the animal later on in adulthood. One of these characteristics is obesity. Obesity is associated with Type II diabetes, and the mice with elevated fetal estradiol levels show evidence of impaired glucose tolerance in later adulthood. These effects are relevant since obesity and diabetes are abnormalities in humans that are increasing.Life Sciences Undergraduate Research Opportunity Progra

Exposure to a Low Dose of Bisphenol A during Fetal Life or in Adulthood Alters Maternal Behavior in Mice

Reproduced with permission from Environmental Health Perspectives.Maternal behavior in mammals is the result of a complex interaction between the lactating dam and her developing offspring. Slight perturbations of any of the components of the mother-infant interaction may result in alterations of the behavior of the mother and/or of the offspring. We studied the effects of exposure of female CD-1 mice to the estrogenic chemical bisphenol A (BPA) during fetal life and/or in adulthood during the last part of pregnancy on subsequent maternal behavior. Pregnant females were fed daily doses of corn oil (controls) or 10 μg/kg body weight BPA during gestation days 14-18. As adults, the prenatally treated female offspring were timemated and again fed either corn oil (controls) or the same doses of BPA on gestation days 14-18, resulting in four treatment groups: controls, prenatal BPA exposure, adult BPA exposure, and both prenatal and adult BPA exposure. Maternal behavior was then observed on postnatal days 2-15 and reflex responses were examined in the offspring. Dams exposed to BPA either as fetuses or in adulthood spent less time nursing their pups and more time out of the nest compared with the control group. Females exposed to BPA both as fetuses and in adulthood did not significantly differ from controls. No alterations in postnatal reflex development were observed in the offspring of the females exposed to BPA. The changes seen in maternal behavior may be the result of a direct effect of BPA on the neuroendocrine substrates underlying the initiation of maternal behavior.This research was supported by grants from NIEHS, NIH (ES08293), to F.V.S. and from the Italian Ministry of University and Scientific Research (MURST-COFIN2000), the University of Parma, and CNR (National Council for Research) to P.P

Small oscillations and the Heisenberg Lie algebra

The Adler Kostant Symes [A-K-S] scheme is used to describe mechanical systems for quadratic Hamiltonians of $\mathbb R^{2n}$ on coadjoint orbits of the Heisenberg Lie group. The coadjoint orbits are realized in a solvable Lie algebra $\mathfrak g$ that admits an ad-invariant metric. Its quadratic induces the Hamiltonian on the orbits, whose Hamiltonian system is equivalent to that one on $\mathbb R^{2n}$. This system is a Lax pair equation whose solution can be computed with help of the Adjoint representation. For a certain class of functions, the Poisson commutativity on the coadjoint orbits in $\mathfrak g$ is related to the commutativity of a family of derivations of the 2n+1-dimensional Heisenberg Lie algebra $\mathfrak h_n$. Therefore the complete integrability is related to the existence of an n-dimensional abelian subalgebra of certain derivations in $\mathfrak h_n$. For instance, the motion of n-uncoupled harmonic oscillators near an equilibrium position can be described with this setting.Comment: 17 pages, it contains a theory about small oscillations in terms of the AKS schem

RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer

BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer. Based on RNA-sequencing we aimed to develop single-sample predictor (SSP) models for conventional clinical markers, molecular intrinsic subtype and risk of recurrence (ROR).MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set and a reserved test set. We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna® in two external cohorts. Prognostic value was assessed using distant recurrence-free interval.ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC was assessed as equivalent. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna® was high for subtype and moderate and high for ROR risk category. In pooled analysis, concordance between SSP and Prosigna® for emulated treatment recommendation for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.ConclusionsSSP models for histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in postmenopausal ER+/HER2-/N0 patients suggested that molecular testing could lead to a changed therapy recommendation for almost one-fifth of patients