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Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells.

ABSTRACT: Benzo(a)pyrene (BaP), a cigarette smoke component, is metabolized to diol esters (BPDE) that bind to DNA and form mutagenic BPDE-DNA adducts. BaP activates stress enzymes including stress-activated protein kinase/jun kinase (MAPK8/9) in embryos, AMP-activated protein kinase alpha1/2 subunits (PRKAA1/2) in somatic cells, and inhibits the proliferation of trophoblast cell lineages. The loss of transcription factor inhibitor of differentiation (ID)2 is required for the initial differentiation of mouse trophoblast stem cells (TSC) in implanting mouse embryo to produce the first placental hormone, chorionic sommatomammotropin (CSH)1. Here we demonstrate that BaP activates PRKAA1/2 and causes ID2 protein loss in TSC in a time- and dose-dependent manner. Although PRKAA1/2 was activated at low BaP doses, PRKAA1/2-dependent ID2 protein loss occurred at a dose that was similar to the threshold that results in a significant decrease in TSC accumulation and decreased fraction of proliferating TSC. This suggests a possible relationship between stress-induced declines in cell accumulation and stem cell differentiation when BaP levels are high. The threshold BaP dose that induces significant ID2 loss is in the range of a 2-3 pack/day habit, suggesting that this mechanism may be involved with implantation failure in smoking women.

SUBMITTER: Xie Y

PROVIDER: S-EPMC3858327 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells.

Xie Yufen Y Abdallah Mazen E ME Awonuga Awoniyi O AO Slater Jill A JA Puscheck Elizabeth E EE Rappolee Dan A DA

Molecular reproduction and development 20100601 6

Benzo(a)pyrene (BaP), a cigarette smoke component, is metabolized to diol esters (BPDE) that bind to DNA and form mutagenic BPDE-DNA adducts. BaP activates stress enzymes including stress-activated protein kinase/jun kinase (MAPK8/9) in embryos, AMP-activated protein kinase alpha1/2 subunits (PRKAA1/2) in somatic cells, and inhibits the proliferation of trophoblast cell lineages. The loss of transcription factor inhibitor of differentiation (ID)2 is required for the initial differentiation of mo ...[more]

PMID: 20422711

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Project description:Polycyclic aromatic hydrocarbons (PAH) are products of incomplete combustion which are ubiquitous pollutants and constituents of harmful mixtures such as tobacco smoke, petroleum and creosote. Animal studies have shown that these compounds exert developmental toxicity in multiple organ systems, including the nervous system. The relative persistence of or recovery from these effects across the lifespan remain poorly characterized. These studies tested for persistence of neurobehavioral effects in AB* zebrafish exposed 5-120 h post-fertilization to a typical PAH, benzo[a]pyrene (BAP). Study 1 evaluated the neurobehavioral effects of a wide concentration range of BAP (0.02-10 μM) exposures from 5 to 120 hpf during larval (6 days) and adult (6 months) stages of development, while study 2 evaluated neurobehavioral effects of BAP (0.3-3 μM) from 5 to 120 hpf across four stages of development: larval (6 days), adolescence (2.5 months), adulthood (8 months) and late adulthood (14 months). Embryonic BAP exposure caused minimal effects on larval motility, but did cause neurobehavioral changes at later points in life. Embryonic BAP exposure led to nonmonotonic effects on adolescent activity (0.3 μM hyperactive, Study 2), which attenuated with age, as well as startle responses (0.2 μM enhanced, Study 1) at 6 months of age. Similar startle changes were also detected in Study 2 (1.0 μM), though it was observed that the phenotype shifted from reduced pretap activity to enhanced posttap activity from 8 to 14 months of age. Changes in the avoidance (0.02-10 μM, Study 1) and approach (reduced, 0.3 μM, Study 2) of aversive/social cues were also detected, with the latter attenuating from 8 to 14 months of age. Fish from study 2 were maintained into aging (18 months) and evaluated for overall and tissue-specific oxygen consumption to determine whether metabolic processes in the brain and other target organs show altered function in late life based on embryonic PAH toxicity. BAP reduced whole animal oxygen consumption, and overall reductions in total basal, mitochondrial basal, and mitochondrial maximum respiration in target organs, including the brain, liver and heart. The present data show that embryonic BAP exposure can lead to neurobehavioral impairment across the life-span, but that these long-term risks differentially emerge or attenuate as development progresses.

Project description:BackgroundBenzo[a]pyrene (B[a]P) belongs to a class of polycyclic aromatic hydrocarbons that serve as micropollutants in the environment. B[a]P has been reported as a probable carcinogen in humans. Exposure to B[a]P can take place by ingestion of contaminated (especially grilled, roasted or smoked) food or water, or inhalation of polluted air. There are reports available that also suggests neurotoxicity as a result of B[a]P exposure, but the exact mechanism of action is unknown.Methodology/principal findingsUsing neuroblastoma cell line and primary cortical neuron culture, we demonstrated that B[a]P has no direct neurotoxic effect. We utilized both in vivo and in vitro systems to demonstrate that B[a]P causes microglial activation. Using microglial cell line and primary microglial culture, we showed for the first time that B[a]P administration results in elevation of reactive oxygen species within the microglia thereby causing depression of antioxidant protein levels; enhanced expression of inducible nitric oxide synthase, that results in increased production of NO from the cells. Synthesis and secretion of proinflammatory cytokines were also elevated within the microglia, possibly via the p38MAP kinase pathway. All these factors contributed to bystander death of neurons, in vitro. When administered to animals, B[a]P was found to cause microglial activation and astrogliosis in the brain with subsequent increase in proinflammatory cytokine levels.Conclusions/significanceContrary to earlier published reports we found that B[a]P has no direct neurotoxic activity. However, it kills neurons in a bystander mechanism by activating the immune cells of the brain viz the microglia. For the first time, we have provided conclusive evidence regarding the mechanism by which the micropollutant B[a]P may actually cause damage to the central nervous system. In today's perspective, where rising pollution levels globally are a matter of grave concern, our study throws light on other health hazards that such pollutants may exert.

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Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells.

Publications

Benzo(a)pyrene causes PRKAA1/2-dependent ID2 loss in trophoblast stem cells.

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