Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment

Chepelev, Nikolai L.; Moffat, Ivy D.; Bowers, Wayne J.; Yauk, Carole L.

doi:10.1016/j.mrrev.2015.03.001

Cited by 91 publications

(60 citation statements)

References 106 publications

(267 reference statements)

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“…Therefore, mutations in the developing brain are induced by lower cumulative doses of BaP than those required for adult cancer formation. Coupled with the observation that in utero BaP exposures as low as 0.3 mg/kg/day impaired neuronal activity in rats (McCallister et al 2008), the developing brain demonstrates unprecedented sensitivity to BaP (Chepelev et al 2015). …”

Section: Discussionmentioning

confidence: 99%

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

Meier

O’Brien

Beal

et al. 2017

Environ Health Perspect

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Background:Mosaicism, the presence of genetically distinct cell populations within an organism, has emerged as an important contributor to disease. Mutational events occurring during embryonic development can cause mosaicism in any tissue, but the influence of environmental factors on levels of mosaicism is unclear.Objectives:We investigated whether in utero exposure to the widespread environmental mutagen benzo[a]pyrene (BaP) has an impact on the burden and distribution of mutations in adult mice.Methods:We used the Muta™Mouse transgenic rodent model to quantify and characterize mutations in the offspring of pregnant mice exposed to BaP during postconception days 7 through 16, covering the major period of organogenesis in mice. Next-generation DNA sequencing was then used to determine the spectrum of mutations induced in adult mice that were exposed to BaP during fetal development.Results:Mutation frequency was significantly increased in the bone marrow, liver, brain, and sperm of first filial generation (F1) males. Developing embryos accumulated more mutations and exhibited higher proportions of mosaicism than exposed adults, particularly in the brain. Decreased sperm count and motility revealed additional negative impacts on the reproductive function of F1 males.Conclusion:In utero exposure to environmental mutagens contributes to somatic and germline mosaicism, permanently affecting both the genetic health of the F1 and the population gene pool.Citation:Meier MJ, O’Brien JM, Beal MA, Allan B, Yauk CL, Marchetti F. 2017. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 125:82–88; http://dx.doi.org/10.1289/EHP211

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Section: Discussionmentioning

confidence: 99%

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

Meier

O’Brien

Beal

et al. 2017

Environ Health Perspect

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“…Mortality and developmental malformations associated with B[a]P exposure are dependent on AHR2 signaling in zebrafish (Incardona, Collier et al 2011; Van Tiem and Di Giulio 2011). AHR dependent metabolism of B[a]P and its resulting metabolites have recently been hypothesized to play a role in B[a]P neurotoxicity (Chepelev, Moffat et al 2015). Here, developmentally B[a]P exposed ahr 2 hu2334 larvae did not exhibit a hyperactive response, suggesting the AHR2-dependent metabolites of B[a]P are responsible for the behavioral as well as the previously reported morphometric phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, both developmental and acute B[a]P exposure is associated with impaired motor activity, and lower cognitive performance in juvenile and adult rodents (Saunders, Das et al 2006; McCallister, Maguire et al 2008; Chen, Tang et al 2012; Cheng, Xia et al 2013; Brown 2016) and anxiety-like behavior in juvenile killifish and zebrafish developmentally exposed to B[a]P-containing PAH mixtures (Vignet, Menach et al 2014; Brown 2016). The observed neurotoxicity is also hypothesized to result from toxic metabolites (Saunders, Das et al 2006; Chepelev, Moffat et al 2015). B[a]P is lipophilic, known to cross the blood-brain-barrier and has been detected, along with B[a]P metabolites, in brain tissue of rodents after exposure (Saunders, Das et al 2006; McCallister, Maguire et al 2008; Yan, Xiang et al 2012; Chepelev, Moffat et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…The observed neurotoxicity is also hypothesized to result from toxic metabolites (Saunders, Das et al 2006; Chepelev, Moffat et al 2015). B[a]P is lipophilic, known to cross the blood-brain-barrier and has been detected, along with B[a]P metabolites, in brain tissue of rodents after exposure (Saunders, Das et al 2006; McCallister, Maguire et al 2008; Yan, Xiang et al 2012; Chepelev, Moffat et al 2015). Short term B[a]P exposure in killifish resulted in an increase in BPDE-dG adduct levels, and both larval and adult killifish exposed to B[a]P also showed a significant increase of nDNA and mtDNA damage, measured as DNA lesions in whole animal or in multiple tissues, including the brain (D Jung 2009).…”

Section: Introductionmentioning

confidence: 99%

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Developmental benzo[a]pyrene (B[a]P) exposure impacts larval behavior and impairs adult learning in zebrafish

Knecht

Truong

Simonich

et al. 2017

Neurotoxicology and Teratology

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Polycyclic aromatic hydrocarbons (PAHs) are produced from incomplete combustion of organic materials or fossil fuels, and are present in crude oil and coal; therefore, they are ubiquitous environmental contaminants present in urban air, dust, soil, and water. It is widely recognized that PAHs pose risks to human health, especially for the developing fetus and infant where PAH exposures have been linked to in-utero mortality, cardiovascular effects, and lower intelligence. Using the zebrafish model, we evaluated the developmental toxicity of benzo[a]pyrene (B[a]P). Zebrafish embryos were exposed from 6–120 hours post fertilization (hpf) to 0.4 and 4 μM B[a]P. The Viewpoint Zebrabox systems were used to evaluate larval photomotor response (LPR) activity and we identified that exposure to 4 μM B[a]P resulted in a hyperactive LPR phenotype. To evaluate the role of aryl hydrocarbon receptor (AHR) in this larval phenotype, we exposed ahr2hu2334 null larvae to 4 μM B[a]P. Though ahr2hu2334 larvae did not display hyperactive swimming, these larvae had a decrease in LPR activity, suggesting AHR2 plays a role in B[a]P induced larval hyperactivity. To determine if developmental B[a]P exposures would produce adult behavioral deficits, a subset of exposed animals was raised to adulthood and tested in a conditioned stimulus test using shuttleboxes. Developmentally exposed B[a]P zebrafish exhibited decreased learning and memory. Together this data demonstrates that developmental B[a]P exposure adversely impacts larval behavior, and learning in adult zebrafish.

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“…These effects do not occur in AHR-null mice, consistent with a role for AHR in mediating dioxin-induced alteration of neuronal differentiation (Gohlke et al, 2009, Latchney et al, 2013). The AHR has also been implicated in the mechanism of neurodevelopmental toxicity caused by other AHR ligands, such as benzo[α]pyrene (Bouayed et al, 2009, Chen et al, 2012, Chepelev et al, 2015, Vignet et al, 2014). In the present study, expression of cyp1a , an indicator of AHR activation, was induced in embryos and larvae following early exposure to PCB126, demonstrating that the AHR pathway was indeed activated through the first five days of development.…”

Section: Discussionmentioning

confidence: 99%

Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior

2016

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Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. The most toxic PCBs are the non-ortho-substituted (“dioxin-like”) congeners that act through the aryl hydrocarbon receptor (AHR) pathway. In humans, perinatal exposure to dioxin-like PCBs is associated with neurodevelopmental toxicity in children. Yet, the full potential for later-life neurobehavioral effects that result from early-life low level exposure to dioxin-like PCBs is not well understood. The objective of this study was to determine the effects of developmental exposure to low levels of dioxin-like PCBs on early-and later-life behavioral phenotypes using zebrafish as a model system. We exposed zebrafish embryos to either vehicle (DMSO) or low concentrations of PCB126 (0.3, 0.6, 1.2 nM) for 20 hours (4–24 hours post fertilization), and then reared them to adulthood in clean water. Locomotor activity was tested at two larval stages (7 and 14 days post fertilization). Adult fish were tested for anxiety-related behavior using the novel tank and shoaling assays. Adult behavioral assays were repeated several times on the same group of fish and effects on intra-and inter-trial habituation were determined. While there was no effect of PCB126 on larval locomotor activity in response to changes in light conditions, developmental exposure to PCB126 resulted in impaired short-and long-term habituation to a novel environment in adult zebrafish. Cyp1a induction was measured as an indicator for AHR activation. Despite high induction at early stages, cyp1a expression was not induced in the brains of developmentally exposed adult fish that showed altered behavior, suggesting that AHR was not activated at this stage. Our results demonstrate the effectiveness of the zebrafish model in detecting subtle and delayed behavioral effects resulting from developmental exposure to an environmental contaminant.

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Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment

Cited by 91 publications

References 106 publications

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

In Utero Exposure to Benzo[ a ]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

Developmental benzo[a]pyrene (B[a]P) exposure impacts larval behavior and impairs adult learning in zebrafish

Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior

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