| Autor: |
Hufgard, Jillian R., Sprowles, Jenna L.N., Pitzer, Emily M., Koch, Sheryl E., Jiang, Min, Wang, Qin, Zhang, Xiang, Biesiada, Jacek, Rubinstein, Jack, Puga, Alvaro, Williams, Michael T., Vorhees, Charles V. |
| Předmět: |
|
| Zdroj: |
Journal of Applied Toxicology; Apr2019, Vol. 39 Issue 4, p603-621, 19p |
| Abstrakt: |
Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three‐coplanar/five‐noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2−/−::Ahrb1 C57BL6/J mice compared with wild‐type mice (Ahrb1 = high AHR affinity). Here we exposed gravid Cyp1a2−/−::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2). PCB‐exposed F1 mice exhibited increased open‐field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long‐term potentiation with no change in spatial learning or memory. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild‐type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de‐/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein. We hypothesized that prenatal exposure to polychlorinated biphenyls (PCBs) at a time of DNA de‐/remethylation would induce F1 neurological and cardiac deficits that would be transmitted epigenetically across generations and be evident in the F3 generation as changes in behavior, hippocampal CA1 long‐term potentiation, cardiac function, RNA expression and DNA methylation. We chose Cyp1a2−/−::Ahrb1 mice because these alleles confer increased susceptibility to PCBs (Ahrb1 has high affinity for the aryl hydrocarbon receptor). F1 PCB‐exposed mice showed behavioral, long‐term potentiation and cardiac functional deficits, but these effects were not recapitulated in F3 mice, nor were there consistent F1 to F3 effects on hippocampal RNA expression or DNA methylation. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
Plný text