Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders.

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 b Cyp1a2(-/-) mice were most sensitive 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 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 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.

Supplemental taurine during adolescence and early adulthood has sex-specific effects on cognition, behavior and neurotransmitter levels in C57BL/6J mice dependent on exposure window.

The mammalian brain goes through final maturation during late adolescence and early adulthood with sex differences in timing. The key cellular processes, including changes in neurotransmitter receptor density and synaptic pruning, make this age uniquely vulnerable to neurotoxic insults. Teenagers and young adults are the major consumers of energy drinks, which contain high levels of taurine and caffeine. Taurine is one of the most abundant amino acids in the central nervous system, but the effects of supplemental taurine consumption during adolescence has not been well studied. We conducted an initial short-term exposure study with 0.12% taurine in drinking water and a long-term exposure dose-response study using 0.06 and 0.12% taurine in male and female C57BL/6J mice. We examined a broad range of cognitive functions and behaviors and measured neurotransmitter levels. We found no significant differences in anxiety, open field locomotor activity, or sensorimotor gating. However, we found impairments in novel object recognition and sex differences in Morris water maze. When taurine treatment stopped before behavioral experiments began, male mice had significant impairments in spatial learning and memory. In the dose-response study when taurine treatment continued throughout behavioral experiments, females had significant impairments. We also found sex differences in neurotransmitter levels with females having higher levels of glutamate, DOPAC and 5-HIAA. We conclude that both females and males are at risk from excess taurine consumption during final brain maturation.