Perfluorooctanoic Acid–Induced Immunomodulation in Adult C57BL/6J or C57BL/6N Female Mice

BackgroundPerfluorooctanoic acid (PFOA), an environmentally persistent compound of regulatory concern, has been reported to reduce antibody responses in mice at a single dose.ObjectiveThe aim of this study was to evaluate PFOA effects on humoral and cellular immunity using standard assays for assessing immune function, and to derive dose–response data.MethodsC57BL/6J mice received 0 or 30 mg PFOA/kg/day for 10 days; half of the exposed groups were switched to vehicle and half continued on PFOA for five days. C57BL/6N mice received 0–30 mg/kg/day of PFOA in drinking water for 15 days. Mice were immunized with sheep red blood cells or sensitized to bovine serum albumin in Freund’s complete adjuvant on day 10 of exposure; immune responses were determined 1 day post-exposure.ResultsWe found that 30 mg PFOA/kg/day given for 10 or 15 days reduced IgM synthesis; serum collected 1 day postexposure contained 8.4 × 104 or 2.7 × 105 ng PFOA/mL, respectively. IgM synthesis was suppressed at exposures ≥ 3.75 mg PFOA/kg/day in a dose-dependent manner, and IgG titers were elevated at 3.75 and 7.5 mg PFOA/kg/day. Serum PFOA at 3.75 mg/kg/day was 7.4 × 104 ng/mL 1 day postexposure, or 150-fold greater than the levels reported in individuals living near a PFOA production site. Using a second-degree polynomial model, we calculated a benchmark dose of 3 mg/kg/day, with a lower bound (95% confidence limit) of 1.75 mg/kg/day. Cell-mediated function was not affected.ConclusionsIgM antibodies were suppressed after PFOA exposure. The margin of exposure for reduced IgM antibody synthesis was approximately 150 for highly exposed human populations

Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Background Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment. Objectives Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

It is well acknowledged from observations in humans that iron deficiency during pregnancy can be associated with a number of developmental problems in the newborn and developing child. Due to the obvious limitations of human studies, the stage during gestation at which maternal iron deficiency causes an apparent impairment in the offspring remains elusive. In order to begin to understand the time window(s) during pregnancy that is/are especially susceptible to suboptimal iron levels, which may result in negative effects on the development of the fetus, we developed a rat model in which we were able to manipulate and monitor the dietary iron intake during specific stages of pregnancy and analyzed the developing fetuses. We established four different dietary-feeding protocols that were designed to render the fetuses iron deficient at different gestational stages. Based on a functional analysis that employed Auditory Brainstem Response measurements, we found that maternal iron restriction initiated prior to conception and during the first trimester were associated with profound changes in the developing fetus compared to iron restriction initiated later in pregnancy. We also showed that the presence of iron deficiency anemia, low body weight, and changes in core body temperature were not defining factors in the establishment of neural impairment in the rodent offspring

FDI and Growth in East Asia: Lessons for Indonesia

Foreign direct investment has been important in the economic growth and global economic integration of developing countries over the last decades. Both Northeast and Southeast Asia, especially the latter, have been part of this development with increasing inflows of FDI and greater foreign participation in their economies. However, Indonesia has been an outlier within the region, with lower inflows of FDI than other countries, especially in manufacturing, and with lower inflows than could be expected from its size and other country characteristics. The inflows of FDI that have taken place have benefited Indonesia and we use the Asian experience to provide some suggestions as to what measures would increase FDI. A relatively poor business environment with inefficient institutions seems to be an important explanation behind the low inflows of FDI

It’s Not Only Rents: Explaining the Persistence and Change of Neopatrimonialism in Indonesia

Indonesia has long been associated with neopatrimonialism, corruption, collusion, and nepotism as the main modi operandi of politics, economics and public administration. Despite various measures and initiatives to fight these practises, little evidence for a significant decline can be found over the years. Rather, longitudinal analysis points to changes in the character of neopatrimonialism. Based on more than 60 in-depth interviews, focus-group discussions, and the analysis of both primary and secondary data, the aim of this article is, first, to describe the changes that have taken place, and, second, to investigate what accounts for these changes. Political economy concepts posit the amount and development of economic rents as the explanatory factor for the persistence and change of neopatrimonialism. This study's findings, however, indicate that rents alone cannot explain what has taken place in Indonesia. Democratisation and decentralisation exert a stronger impact

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Immunotoxicity, Immune Dysfunction, and Chronic Disease

XVI, 452 p.online resource

Serum Supplementation Modulates the Effects of Dibutyltin on Human Natural Killer Cell Function

Natural killer (NK) cells are a subset of lymphocytes capable of killing tumor cells, virally infected cells and antibody-coated cells. Dibutyltin (DBT) dichloride is an organotin used as a stabilizer in polyvinylchloride (PVC) plastics and as a deworming product in poultry. DBT may leach from PVC water supply pipes and therefore poses a potential risk to human health. We previously reported diminished NK cells lysis of tumor cells following exposure to DBT in serum-free cell culture medium. However, under in vivo conditions, circulating cells will be exposed to DBT in the presence of 100% plasma; thus we investigated whether serum supplementation and incubation time modulates DBT effects on NK cell killing and the accumulation of DBT in freshly isolated NK cells, to determine whether a serum-free model accurately predicts possible effects of DBT on human NK cells under in vivo conditions. Lytic function was decreased by approximately 35% at an intracellular DBT (DBTi) concentration of 200μM and nearly complete loss of lytic function was observed at DBTi above 300μM for one h. However, an intracellular concentration of 50μM DBT, achieved over 24 h of exposure in 50% serum, reduced lytic function by 50%. Thus, conditions that reflect prolonged contact with circulating DBT, in the presence of serum, suggest that NK cell activity is decreased at lower DBTi. These data indicate that the model is useful in predicting potential human effects of relatively low DBTi concentrations