Motorcycle exhaust (ME) is a health hazard in urban areas where motorcycles are a popular means of transportation. ME contains many protoxicants and procarcinogens including benzo(a)pyrene, benz(a)anthracene, benzene, and 1,3-butadiene which require metabolic activation by cytochrome P450 (CYP). The long-term goal of this research plan is to study the toxicological profile and mechanism of action of ME to which humans may be exposed. Preliminary studies from this laboratory indicate that exposure of male rats to ME produces cardiotoxicity, induces hepatic CYP2E1, and inhibits offspring CYP1A2 expression. ME exposure of pregnant female rats elicits maternal toxicity and disrupts offspring growth and development. The main hypothesis of this proposal is that ME causes systemic effect and transgenerational toxicity. The proposed studies will be carried out usingWistar rats as the experimental model. Animals will be exposed to 1:10 diluted ME from 9 to 10 a.m. and 4 to 5 p.m. daily, aiming to provide more environmentally realistic conditions. In subchronic studies, male rats will be exposed to ME five days a week for 8 weeks. In in utero exposure studies, pregnant female rats will be exposed to ME from gestational day 7 to 20. This three-year proposal has four specific aims which are to: 1. Determine the cardiotoxicity of subchronic ME exposure; 2. Investigate the effects of subchronic ME exposure on CYP2E1 and trichloroethylene toxicity; 3. Explore the ability of paternal ME exposure to modulate CYP1A2 and aryl hydrocarbon receptor (AHR) signaling; and 4. Determine the effects of in utero ME exposure on reproductive development. The proposed cardiotoxicity studies will generate information regarding dose-response, reversibility, and mechanistic role of oxidative stress in the adverse ME effects. The enzyme induction studies will determine the ability of ME to induce CYP2E1 in liver and testis and to investigate the effects of enzyme induction on hepatic and testicular toxicities of trichloroethylene. The proposed drug metabolism studies will determine the modulatory effects of paternal ME exposure on offspring CYP1A2 and its AHR transcriptional regulation and explore the pathway of the transgenerational modulation. The in utero ME studies will determine the maternal toxicity of gestational ME exposure and the adverse effects of the exposure on growth and sexual development of male and female offspring. The results of the proposed studies will identify the target organs of ME systemic toxicity and characterize the developmental toxicities of paternal and gestational ME exposures. Seeing that a vast number of people are exposed to ME, a better understanding of ME toxicity and mechanism of action is potentially important for public health and environmental medicine.
|Effective start/end date||8/1/11 → 7/31/13|
- Motorcycle exhaust
- CYP2E1 induction
- CYP1A2 regulation
- _x000d_ reproductive development toxicity