Structure-Activity Relationship of Lower Chlorinated Biphenyls and Their Human-Relevant Metabolites for Astrocyte Toxicity.

Exposure to polychlorinated biphenyls (PCBs) is associated with developmental neurotoxicity and neurodegenerative disorders; however, the underlying mechanisms of pathogenesis are unknown. Existing literature has focused mainly on using neurons as a model system to study mechanisms of PCB-mediated neurotoxicity, overlooking the role of glial cells, such as astrocytes. As normal brain function is largely astrocyte-dependent, we hypothesize that astrocytes play an important role in PCB-mediated injury to neurons. We assessed the toxicity of two commercial PCB mixtures, Aroclor 1016 and Aroclor 1254, and a non-Aroclor PCB mixture found in residential air called the Cabinet mixture, all of which contain lower chlorinated PCBs (LC-PCBs) found in indoor and outdoor air. We further assessed the toxicity of five abundant airborne LC-PCBs and their corresponding human-relevant metabolites in vitro models of astrocytes, namely, the C6 cell line and primary astrocytes isolated from Sprague-Dawley rats and C57BL/6 mice. PCB52 and its human-relevant hydroxylated and sulfated metabolites were found to be the most toxic compounds. No significant sex-dependent cell viability differences were observed in rat primary astrocytes. Based on the equilibrium partitioning model, it was predicted that the partitioning of LC-PCBs and their corresponding metabolites in biotic and abiotic compartments of the cell culture system is structure-dependent and that the observed toxicity is consistent with this prediction. This study, for the first time, shows that astrocytes are sensitive targets of LC-PCBs and their human-relevant metabolites and that further research to identify mechanistic targets of PCB exposure in glial cells is necessary.

Probing the Role of CYP2 Enzymes in the Atropselective Metabolism of Polychlorinated Biphenyls Using Liver Microsomes from Transgenic Mouse Models.

Chiral polychlorinated biphenyls (PCB) are environmentally relevant developmental neurotoxicants. Because their hydroxylated metabolites (OH-PCBs) are also neurotoxic, it is necessary to determine how PCB metabolism affects the developing brain, for example, in mouse models. Because the cytochrome P450 isoforms involved in the metabolism of chiral PCBs remain unexplored, we investigated the metabolism of PCB 91 (2,2',3,4',6-pentachlorobiphenyl), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 132 (2,2',3,3',4,6'-hexachlorobiphenyl), and PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl) using liver microsomes from male and female Cyp2a(4/5)bgs-null, Cyp2f2-null, and wild-type mice. Microsomes, pooled by sex, were incubated with 50 µM PCB for 30 min, and the levels and enantiomeric fractions of the OH-PCBs were determined gas chromatographically. All four PCB congeners appear to be atropselectively metabolized by CYP2A(4/5)BGS and CYP2F2 enzymes in a congener- and sex-dependent manner. The OH-PCB metabolite profiles of PCB 91 and PCB 132, PCB congeners with one para-chlorine substituent, differed between null and wild-type mice. No differences in the metabolite profiles were observed for PCB 95 and PCB 136, PCB congeners without a para-chlorine group. These findings suggest that Cyp2a(4/5)bgs-null and Cyp2f2-null mice can be used to study how a loss of a specific metabolic function (e.g., deletion of Cyp2a(4/5)bgs or Cyp2f2) affects the toxicity of chiral PCB congeners.

Is radiation-free diagnostic monitoring of adolescent idiopathic scoliosis feasible using upright positional magnetic resonance imaging?

STUDY DESIGN: Prospective clinical trial. OBJECTIVE: The purpose of this study was to determine if an upright positional magnetic resonance imaging (MRI) protocol could produce reliable spinal curvature images and measurements compared with traditional radiograph. SUMMARY OF BACKGROUND DATA: Concerns about the oncological potential from cumulative doses of ionizing radiation in children and adolescents being monitored for adolescent idiopathic scoliosis (AIS) initiated a search for radiation-free diagnostic imaging modalities, including MRI. We submit that upright, positional MRI (uMRI) produces reliable spinal curvature images compared with traditional radiograph. METHODS: Twenty-five consecutive patients (16 female; 9 male; average age, 14.6 yr; range, 12-18 yr) with a diagnosis of AIS were enrolled. Average major curve magnitude was 30° (range, 6°-70°). Subjects received anterior-posterior and lateral plain radiographical scoliosis imaging followed within 1 week by uMRI. MRI data acquisition was performed in less than 7 minutes. Two independent observers performed all Cobb angle, T5-T12 kyphosis, and vertebral rotation measurements for comparison. The Pearson correlation method was performed to compare radiograph to uMRI measurements, while inter-rater and intrarater correlations were performed to assess reliability. RESULTS: We found outstanding correlation between all plain film radiography and uMRI measurements (P = 0.01); major Cobb angles (R = 0.901), minor Cobb angles (R = 0.838), and kyphosis (R = 0.943). Inter-rater reliability for both radiographical and MRI measurements of major Cobb angles (R = 0.959, 0.896, respectively), minor Cobb angles (R = 0.951, 0.857, respectively), and vertebral rotation (R = 0.945) were outstanding. Intrarater reliability for both radiographical and MRI measurements of major Cobb angles (R = 0.966, 0.966, respectively) and minor Cobb angles (R = 0.945, 0.943, respectively) were also outstanding. CONCLUSION: Our results show that uMRI is capable of producing coronal and sagittal plane measurements that highly correlate with traditional plain film radiographical measurements. This, in addition to reliable vertebral rotation measurements, makes uMRI a valuable, radiation-free alternative/substitute for diagnostic evaluation in AIS.

Maximal pulmonary recovery after spinal fusion for adolescent idiopathic scoliosis: how do anterior approaches compare?

STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To compare the relative rates of pulmonary recovery and maximal pulmonary function with surgical approach. SUMMARY OF BACKGROUND DATA: Anterior versus posterior spinal fusion (ASF, PSF) for the treatment of adolescent idiopathic scoliosis (AIS) has been debated. Although procedures that violate the chest wall may compromise pulmonary function, lung function continues to improve after surgery at variable rates depending upon surgical approach. METHODS: We reviewed the medical records from one hundred fifty nine AIS patients (age 15.6±2.2; 113 women; 46 men) treated with spinal fusion from 2003 to 2007 by a single surgeon. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and radiographic measurements were evaluated before surgery and at 1, 3, 6, 12, and 24-months follow-up on average. Four surgical groups were compared: PSF, ASF (open thoracoabdominal approach for thoracolumbar curvature), video-assisted thoracoscopic surgical release with instrumentation (VATS-I), and VATS with PSF. FEV1 and FVC were fitted to model to evaluate the immediate postoperative pulmonary function (Yo), maximal recovery (Plateau), and rate (K) of pulmonary improvement. RESULTS: Patients in each surgical subgroup were as follows: PSF (Lenke 1: n=50, Lenke 2,3: n=20), ASF (Lenke 5, n=35), VATS-I (Lenke 1=31, Lenke 3=1), and VATS+PSF (Lenke1: n=9, Lenke 2-6: n=13). Early postoperative pulmonary function was higher with ASF and PSF as compared to both VATS groups (P<0.05). Comparing all curve types, VATS-I showed a small decline of absolute FEV1 compared to PSF at 2-years follow-up. Comparing thoracic curves, however, no differences in FEV1 or FVC were noted at 6 to 12 months until 2-years follow-up. The rate of recovery (K) was equivalent for all surgical approaches and curve types. CONCLUSION: Compared to ASF or PSF, VATS procedures showed an initial decline in pulmonary function, which resolved fully by 6- to 12-months follow-up. Modest declines in maximal pulmonary function with VATS-I were seen when comparing all curve types together but not when comparing Lenke 1 curves alone. VATS procedures for thoracic scoliosis and open approaches for thoracolumbar curve types were associated with minimal to no permanent deficits.