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

Abstract

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.

Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

“…Gestational and lactational exposure to a mixture of DL (PCBs 77, 105, 118, 126, and 169) and NDL (PCBs 138, 153, and 180) congeners at 5.6 mg/kg/d in the maternal diet reduced serum thyroxine (T4) at PND 14 in offspring of all three genotypes. However, Ahr b /Cyp1a2 -/mice exhibited a greater T4 reduction than the other two genotypes [177]. Postnatal development of the cerebellum is particularly sensitive to TH insufficiency [175][176][177][178], and consistent with this, PCB-exposed Ahr b /Cyp1a2 -/mice exhibited defects in cerebellar structure at PND 25 [177].…”

“…However, Ahr b /Cyp1a2 -/mice exhibited a greater T4 reduction than the other two genotypes [177]. Postnatal development of the cerebellum is particularly sensitive to TH insufficiency [175][176][177][178], and consistent with this, PCB-exposed Ahr b /Cyp1a2 -/mice exhibited defects in cerebellar structure at PND 25 [177]. In other studies by this group, exposure to this same PCB mixture on GD 10 and PND 5 resulted in learning and memory deficits in NOR and MWM tasks in both Ahr b /Cyp1a2 -/- [178] and Ahr d /Cyp1a2 -/-mice [179], enhanced startle response in Ahr d /Cyp1a2 -/mice [179], and increased locomotor activity in Ahr b /Cyp1a2 -/mice [178].…”

“…This conclusion is supported by a recent epidemiological investigation of PCBs as risk factors for ASD that found no association between developmental exposure to DL PCBs and neuropsychiatric deficits in children, but did identify an association, albeit weak, between NDL PCBs, specifically those that are RyR-active, and increased risk of ASD diagnosis [19]. While the data currently available do not support a major role for DL PCBs in PCB developmental neurotoxicity, they also do not rule out the possibility that DL PCBs play some role, possibly in modifying neurotoxic responses to NDL PCBs [177,179]. However, clearly there is a need for more studies evaluating potential neurodevelopmental effects of individual PCB congeners and mixtures that better replicate contemporary human exposures than the legacy Aroclor mixtures.…”

“…Four allelic variants of Ahr have been described in laboratory mice [175,176], and, of these, the higher-affinity variants (e.g., AhR b variants) appear to enhance susceptibility to the neurotoxic effects of PCBs via induction of cytochrome P450 (CYP) enzyme families 1A and 1B [176], which are believed to oxidize coplanar PCBs and non-coplanar PCBs, respectively [8]. This hypothesis is based on comparative studies of PCB developmental neurotoxicity in transgenic mice that express high-affinity AhR/wild-type CYP1A2 (Ahr b /Cyp1a2 +/+ ) vs. mice nullizygous for Cyp1a2 that express either the high-or low-affinity AhR (Ahr b /Cyp1a2 -/and Ahr d /Cyp1a2 -/-, respectively) [177]. Gestational and lactational exposure to a mixture of DL (PCBs 77, 105, 118, 126, and 169) and NDL (PCBs 138, 153, and 180) congeners at 5.6 mg/kg/d in the maternal diet reduced serum thyroxine (T4) at PND 14 in offspring of all three genotypes.…”

Introduction to mammalian genome special issue: the combined role of genetics and environment relevant to human disease outcomes

“…This study not only increased the power of GWAS, but also provided critical mechanistic underpinning to the identified susceptibility loci. The interplay between the status of aryl hydrocarbon receptor (AHR), cytochrome P450 1a2, exposure to polychlorinated biphenyls (PCB), and neurotoxicity was explored using genetically-modified mouse models by Klinefelter et al (Klinefelter et al 2018). The authors were especially interested in the effects of in utero exposures and showed that AHR is a modifier of developmental neurotoxicity of PCB, but not for Parkinson’s disease.…”