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

Abstract

(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.

Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

“…Thyroid hormone receptor beta (THRB) was among the top 10 transcription factor motifs enriched within placenta and brain PCB DMRs in females, with lower ranked enrichments in males. DL PCBs differ from NDL PCBs in that their primary mechanism involves binding to the aryl hydrocarbon receptor (AHR), which is then bound by the aryl hydrocarbon receptor nuclear translocator (ARNT), also known as hypoxia-inducible factor 1b (HIF1B), and translocated to the nucleus to activate genes involved in xenobiotic metabolism, such as cytochrome P450s (Calo `et al, 2014;Kim et al, 2015;Klinefelter et al, 2018;Matsushita et al, 1993;Seok et al, 2017). HIF1B was one of the top 10 transcription factor motifs enriched in PCB DMRs from female placenta, male placenta, and female brain and had a lower ranked enrichment in male brain.…”

Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice

“…29−31 Genetic differences in CYP1A and CYP1B enzymes alter the toxicokinetics of PCBs and affect PCB developmental neurotoxicity. 32,33 Finally, maternal CYP1A2 levels in the liver correlated with memory and learning deficits caused by PCB exposure. 34 However, these mouse models cannot be used to study the developmental neurotoxicity of PCB 95 because CYP2 and not CYP1 enzymes metabolize PCB congeners with multiple ortho chlorine substituents.…”

Altered Microbiota-GALT Communication in IBD and ASD: Changes in IELs and AhR/ARNT Gene Polymorphism

“…In that context, the examination of a variety of naturally occurring vegetable-derived dietary compounds, like indole-3-carbinol processed in the stomach, that can directly activate or inhibit AhR signaling pathways [75] seems especially promising. Furthermore, allelic differences in AhR also affect the susceptibility to developmental PCB neurotoxicity and lead to greater impairments in learning and memory and motor function [81].…”

“…The emerging role of IEL associated-AhRs and ARNT polymorphism in ASD Among the AhR environmental ligands are the endocrine disruptors like polychlorinated biphenyls (PCB) implicated in autistic pathology[80]. Animal studies have linked AhR to the regulation of the developmental toxicity to PCB[81] based on the observation that mice deficient in AhR show increased sensitivity to the developmental exposure to these environmental toxicants.…”