Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with newly discovered sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but highly exposed adults reportedly have an increased risk of Parkinson's disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect sensitivity to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity Ahr Cyp1a2(-/-) mice were most sensitive compared with poor-affinity Ahr Cyp1a2(-/-) and wild-type Ahr Cyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological, and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated toxicity with reduced thymus and spleen weights and significantly reduced thyroxine at P14 in PCB-exposed pups. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immunostaining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity Ahr Cyp1a2(-/-) while Ahr Cyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson's disease.

Corticospinal (CS) neurons in layer V of the sensorimotor cortex are essential for voluntary motor control. Those neurons project axons to specific segments along the rostro-caudal axis of the spinal cord, and reach their spinal targets by sending collateral branches interstitially along axon bundles. Currently, little is known how CS axon collaterals are formed in the proper spinal cord regions. Here, we show that the semaphorin3A (Sema3A)-neuropilin-1 (Npn-1) signaling pathway is an essential negative regulator of CS axon collateral formation in the spinal cord from mice of either sex. Sema3A is expressed in the ventral spinal cord, whereas CS neurons express Npn-1, suggesting that Sema3A might prevent CS axons from entering the ventral spinal cord. Indeed, the ectopic expression of Sema3A in the spinal cord in vivo inhibits CS axon collateral formation, whereas Sema3A or Npn-1 mutant mice have ectopic CS axon collateral formation within the ventral spinal cord compared with littermate controls. Finally, Npn-1 mutant mice exhibit impaired skilled movements, likely because of aberrantly formed CS connections in the ventral spinal cord. These genetic findings reveal that Sema3A-Npn-1 signaling-mediated inhibition of CS axon collateral formation is critical for proper CS circuit formation and the ability to perform skilled motor behaviors.

(150-250 wds)Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinson's disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity Ahr b Cyp1a2(-/-) mice were most susceptible compared with poor-affinity Ahr d Cyp1a2(-/-) and wild type Ahr b Cyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity Ahr d Cyp1a2(-/-) while Ahr b Cyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson's disease.