Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11‐q13 duplication autism spectrum disorder

Abstract

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) that bioaccumulate in lipid-rich tissues are of concern as developmental neurotoxicants. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental factors implicated in autism-spectrum disorders. The relationship between POP levels and DNA methylation patterns in individuals with and without neurodevelopmental disorders has not been previously investigated. In this study, a total of 107 human frozen post-mortem brain samples were analyzed for 8 PCBs and 7 PBDEs by GC-micro electron capture detector and GC/MS using negative chemical ionization. Human brain samples were grouped as neurotypical controls (n=43), neurodevelopmental disorders with known genetic basis (n=32, including Down, Rett, Prader-Willi, Angelman, and 15q11-q13 duplication syndromes), and autism of unknown etiology (n=32). Unexpectedly, PCB 95 was significantly higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls. Interestingly, samples with detectable PCB 95 levels were almost exclusively those with maternal 15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome. When sorted by birth year, Dup15q samples represented five out of six of genetic neurodevelopmental samples born after the 1976 PCB ban exhibiting detectable PCB 95 levels. Dup15q was the strongest predictor of PCB 95 exposure over age, gender, or year of birth. Dup15q brain showed lower levels of repetitive DNA methylation measured by LINE-1 pyrosequencing, but methylation levels were confounded by year of birth. These results demonstrate a novel paradigm by which specific POPs may predispose to genetic copy number variation of 15q11-q13.

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

“…Deficits in children have included lowered IQ scores, impaired learning and memory, and attention deficit (Jacobson and Jacobson, 1996;Lonky et al, 1996;Stewart et al, 2008). It is well recognized that PCB residues in these samples are complex mixtures but neurotoxic outcomes due to PCB mixture exposure have been largely ascribed to NDL congeners because they are found in relatively high concentrations in the brains of human and experimental animals that display neuropsychological deficits (Mitchell et al, 2012;Pessah et al, 2010) NDL PCBs also constitute the majority of the total PCB burden in both human and environmental samples (Hwang et al, 2001(Hwang et al, , 2006Marek et al, 2013;Stahl et al, 2009) and further understanding the contribution of the RyR, alone or in combination with other modes of NDL PCB neurotoxicity (see "Introduction" section), would help further elucidate risks in human populations.…”

Early exposure to bisphenol A alters neuron and glia number in the rat prefrontal cortex of adult males, but not females

“…Examples include studies investigating early exposure to phthalates, polybrominated diphenyl ethers, and polychlorinated biphenyls (Larsson et al, 2009; Miodovnik et al, 2011; Mitchell et al, 2012; Testa et al, 2012; Woods et al, 2012). Although the magnitude seen in the present study is relatively small, there is evidence that large increases in neurons and glia are found in human males diagnosed with autism (Courchesne et al 2011; Edmonson et al, 2014).…”

Advancing parental age and autism: multifactorial pathways

“…21,No. 2 contaminant known to influence neurodevelopment) strongly predicted maternal 15q11-q13 duplication (one of the most common CNV findings in ASD cases), and samples with 15q11-q13 showed some evidence of DNA hypomethylation [66]. These findings suggest a potential epigenetic mechanism by which environmental exposures that accumulate with AMA may lead to de novo mutations with relevance to ASD risk.…”