The Navigation Guide—Evidence-Based Medicine Meets Environmental Health: Systematic Review of Human Evidence for PFOA Effects on Fetal Growth

Background: The Navigation Guide methodology was developed to meet the need for a robust method of systematic and transparent research synthesis in environmental health science. We conducted a case study systematic review to support proof of concept of the method.Objective: We applied the Navigation Guide systematic review methodology to determine whether developmental exposure to perfluorooctanoic acid (PFOA) affects fetal growth in humans.Methods: We applied the first 3 steps of the Navigation Guide methodology to human epidemiological data: 1) specify the study question, 2) select the evidence, and 3) rate the quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using prespecified criteria. We evaluated each study for risk of bias and conducted meta-analyses on a subset of studies. We rated quality and strength of the entire body of human evidence.Results: We identified 18 human studies that met our inclusion criteria, and 9 of these were combined through meta-analysis. Through meta-analysis, we estimated that a 1-ng/mL increase in serum or plasma PFOA was associated with a –18.9 g (95% CI: –29.8, –7.9) difference in birth weight. We concluded that the risk of bias across studies was low, and we assigned a “moderate” quality rating to the overall body of human evidence.Conclusion: On the basis of this first application of the Navigation Guide systematic review methodology, we concluded that there is “sufficient” human evidence that developmental exposure to PFOA reduces fetal growth.Citation: Johnson PI, Sutton P, Atchley DS, Koustas E, Lam J, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide—evidence-based medicine meets environmental health: systematic review of human evidence for PFOA effects on fetal growth. Environ Health Perspect 122:1028–1039; http://dx.doi.org/10.1289/ehp.1307893     

The Navigation Guide—Evidence-Based Medicine Meets Environmental Health: Integration of Animal and Human Evidence for PFOA Effects on Fetal Growth

Background: The Navigation Guide is a novel systematic review method to synthesize scientific evidence and reach strength of evidence conclusions for environmental health decision making.Objective: Our aim was to integrate scientific findings from human and nonhuman studies to determine the overall strength of evidence for the question “Does developmental exposure to perfluorooctanoic acid (PFOA) affect fetal growth in humans?”Methods: We developed and applied prespecified criteria to systematically and transparently a) rate the quality of the scientific evidence as “high,” “moderate,” or “low”; b) rate the strength of the human and nonhuman evidence separately as “sufficient,” “limited,” “moderate,” or “evidence of lack of toxicity”; and c) integrate the strength of the human and nonhuman evidence ratings into a strength of the evidence conclusion.Results: We identified 18 epidemiology studies and 21 animal toxicology studies relevant to our study question. We rated both the human and nonhuman mammalian evidence as “moderate” quality and “sufficient” strength. Integration of these evidence ratings produced a final strength of evidence rating in which review authors concluded that PFOA is “known to be toxic” to human reproduction and development based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species.Conclusion: We concluded that developmental exposure to PFOA adversely affects human health based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species. The results of this case study demonstrate the application of a systematic and transparent methodology, via the Navigation Guide, for reaching strength of evidence conclusions in environmental health.Citation: Lam J, Koustas E, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide—evidence-based medicine meets environmental health: integration of animal and human evidence for PFOA effects on fetal growth. Environ Health Perspect 122:1040–1051; http://dx.doi.org/10.1289/ehp.1307923     

Brain glucose and acetoacetate metabolism: a comparison of young and older adults

The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min⁻¹) of glucose (Kg) and acetoacetate (Ka) were significantly lower (−11 ± 6%; [p = 0.005], and −19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.     

Chondroitin sulfate proteoglycans in the developing central nervous system. I. Cellular sites of synthesis of neurocan and phosphacan

We have used in situ hybridization histochemistry to examine the cellular sites of synthesis of two major nervous tissue proteoglycans, neurocan and phosphacan, in embryonic and postnatal rat brain and spinal cord. Both proteoglycans were detected only in nervous tissue. Neurocan mRNA was evident in neurons, including cerebellar granule cells and Purkinje cells, and in neurons of the hippocampal formation and cerebellar nuclei. In contrast, phosphacan message was detected only in astroglia, such as the Golgi epithelial cells of the cerebellum. At embryonic day 13–16, phosphacan mRNA is largely confined to areas of active cell proliferation (e.g., the ventricular zone of the ganglionic eminence and septal area of the brain and the ependymal layer surrounding the central canal of the spinal cord) as well as being present in the roof plate. The distribution of neurocan message is more widespread, extending to the cortex, hippocampal formation, caudate putamen, and basal telencephalic neuroepithelium, and neurocan mRNA is present in both the ependymal and mantle layers of the spinal cord but not in the roof plate. The presence of neurocan mRNA in areas where the proteoglycan is not expressed suggests that the short open reading frame in the 5′-leader of neurocan may function as a cis-acting regulatory signal for the modulation of neurocan expression in the developing central nervous system. © 1996 Wiley-Liss, Inc.     

Heat shock increases antigenic peptide generation but decreases antigen presentation

The heat shock response is a universal and highly conserved cellular response to stress. We describe here the effect of elevated temperature on the capacity of B cells to present antigen. Heat shock markedly affects the ability of these cells to process and present tetanus toxin to class II-restricted T cell clones. Inhibition of antigen presentation is due neither to a modification of antigen capture nor to a variation of major histocompatibility complex (MHC) class II molecule synthesis and cell surface expression. Stressed and nonstressed B cells are able to present peptides loaded at the cell surface with the same efficiency. Nevertheless, heat shock leads to an increase of antigen peptide generation in subcellular compartments; an enhancement of cathepsin B activity is also observed. These data suggest that such a stress induces a failure in the intracellular peptide loading onto MHC class II molecules.     

Mechanical stretch induces myelin protein loss in oligodendrocytes by activating Erk1/2 in a calcium-dependent manner

Myelin loss in the brain is a common occurrence in traumatic brain injury (TBI) that results from impact-induced acceleration forces to the head. Fast and abrupt head motions, either resulting from violent blows and/or jolts, cause rapid stretching of the brain tissue, and the long axons within the white matter tracts are especially vulnerable to such mechanical strain. Recent studies have shown that mechanotransduction plays an important role in regulating oligodendrocyte progenitors cell differentiation into oligodendrocytes. However, little is known about the impact of mechanical strain on mature oligodendrocytes and the stability of their associated myelin sheaths. We used an in vitro cellular stretch device to address these questions, as well as characterize a mechanotransduction mechanism that mediates oligodendrocyte responses. Mechanical stretch caused a transient and reversible myelin protein loss in oligodendrocytes. Cell death was not observed. Myelin protein loss was accompanied by an increase in intracellular Ca²⁺ and Erk1/2 activation. Chelating Ca²⁺ or inhibiting Erk1/2 activation was sufficient to block the stretch-induced loss of myelin protein. Further biochemical analyses revealed that the stretch-induced myelin protein loss was mediated by the release of Ca²⁺ from the endoplasmic reticulum (ER) and subsequent Ca²⁺-dependent activation of Erk1/2. Altogether, our findings characterize an Erk1/2-dependent mechanotransduction mechanism in mature oligodendrocytes that de-stabilizes the myelination program.