Unravelling the Relationship between Body Mass Index and Polychlorinated Biphenyl Concentrations Using a Mechanistic Model

Human biomonitoring (HBM) often reveals statistical associations between persistent organic pollutant (POP) concentrations and body mass index (BMI). Both negative and positive associations have been observed, which has been hypothesized to reflect variable toxicokinetics in lean and obese individuals during times of increasing and decreasing exposure. We examined this hypothesis and assessed the influence of the obesity epidemic on time trends in human exposure to polychlorinated biphenyls (PCB) at the population level using a mechanistic modeling approach and data from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Using model results for PCB-153, we simulated cross-sectional body burden versus BMI trends (CBBTs), as well as population level body burden versus time trends. Negative associations between PCB-153 concentrations and BMI are predicted for all birth cohorts in HBM studies conducted in the 1990s, while for future cross-sectional studies, we predict negative or positive relationships depending on the age group sampled. At the population level, demographic changes such as the obesity epidemic and population aging had only marginal influence on the simulated rate of decline in PCB-153 concentrations between 1980 and 2010. Mechanistic bioaccumulation models can help unravel relationships between age, BMI, and POP concentrations, informing efforts to understand potential obesogenic effects of POPs

BergDecompData

Litter decomposition data and associated site descriptions and climate data for the 20 sites used in the stud

BergDecompCode

Statistical freeware package R code used for analyzing the associated data file in this package and drawing the graphics in the associated manuscript

BergDecompReadMe

ReadMe file describing the content of the associated data file and R code file for the stud

Gene-environment interactions.

<p>^a major/minor allele</p><p>^b odds ratio</p><p>^c adjusted for age and gender</p><p>^d ≥ 17 pack years (median)</p><p>^e lifetime exposure to pesticide >26 days.</p><p>Gene-environment interactions.</p

Loss of <i>Usp9x</i> reduces neuronal outgrowth.

<p>Embryonic hippocampal neurons were isolated, transfected with a plasmid encoding Enhanced Green Fluorescent Protein, and grown in-vitro for 3, 5 or 7 days. (a) Example immunofluorescent images of wildtype (Nes-<i>Usp9x^+/Y</i>) and null (Nes-<i>Usp9x^−/Y</i>) neurons resolved using GFP expression (Green) and co-stained with the axonal and dendritic specific antibodies, TAU1 (cyan) and MAP2 (red) respectively. (b–c) Morphometric analysis was employed to record mean primary axonal length (b) and number of neurite termini (c). *p<0.05 by student 2-tailed t-test.</p

Loss of <i>Usp9x</i> disrupts the architecture of the embryonic neocortex.

<p>The Nestin-cre mediated deletion of Usp9x (B,D) results in loss of demarcation between the cells of the ventricular and sub-ventricular zones (VZ/SVZ), the more disperse cellular density of the intermediate zone (IZ) and the neurons of the cortical plate (CP) seen in control littermates (A,C). C and D are higher magnification images of A and B, respectively. Nestin (E,F) and BLBP (G,H) staining in E18.5 embryos indicated that neural progenitors were more loosely organized in the VZ/SVZ. Neurons of the cortical plate were disorganized in the absence of <i>Usp9x</i> (J) compared with littermates (I). Nissl stain of <i>Usp9x^+/Y</i> (A,C,G) and <i>Usp9x^−/Y</i> (B,D,H) in E16.5 embryos (A–D, G–H). V = ventricle. Scale bar = 100 µm (A), 50 µm (C), 40 µm (E), 100 µm (G), 40 µm (I).</p

<i>Usp9x</i> loss affects neuronal and astrocytic projections.

<p>NF160 antibodies decorate axonal projection from the neocortex (Nc) to the hippocampus (Hp) in E18.5 Nes-<i>Usp9x^+/Y</i> mice (A). These projections were absent in Nes-<i>Usp9x^−/Y</i> mice (B). GFAP staining is reduced in both the hippocampus and neocortex of E18.5 <i>Usp9x ^−/Y</i> embryos (D) compared with littermate controls (C). In the hippocampus GFAP-labeled projections extended toward the CA3 region in control embryos (arrowhead in E) but not in the absence of <i>Usp9x</i> (F). Scale bar = 20 µm (A,B), 160×µm (C,D), 80×µm (E,F).</p

Loss of <i>Usp9x</i> disrupts TGF-β signalling in hippocampal neurons.

<p>(a–b) TGF-β luciferase reporter assays conducted in either wildtype (Nes-<i>Usp9x^+/Y</i>) or null (Nes-<i>Usp9x^−/Y</i>) embryonic hippocampal neuronal cultures. Hippocampal neurons were isolated and transfected with both renilla control and pGL3-TGF-β luciferase reporter plasmids. (a) Cells were grown for 3 days before analysis using dual-luciferase reporter assays and data normalised relative to wildtype readings. (b) Luciferase reporter activity in response to increasing concentrations of TGF-β. Data normalised to controls in the absence of TGF-β. All luciferase data from 6 biological replicates (i.e. cultures isolated from 6 <i>Usp9x^+/y</i> and 6 <i>Usp9x^−/Y</i> embryos). (c) Response of established TGFβ target genes in presence or absence of <i>Usp9x</i>, analysed by RT-qPCR. Isolated hippocampal neurons grown for 2 days prior to the addition of 1 ng/ml TGF-β. (d–e). Morphological analysis of hippocampal neurons exposed to 1 ng/ml TGF-β in the presence or absence of Usp9x. (d) Comparison of mean primary axonal length. (e). Comparison of number of neurite termini.</p

GeoChip 4.0 Data

Log-transformed results for all GeoChip functional genes