Interactions of Fine Particulate Matter Exposure and Gonadal Toxicity on Alzheimer s Disease Progression
Abstract
Background/Rationale: Fine particulate matter air pollution (PM2.5) is generated by burning of waste, such as was done at U.S. bases in Iraq and Afghanistan in so-called burn pits. Exposure to PM2.5 from burning or combustion of waste, fossil fuels, wood, and other materials, has been associated with increased risk of heart and lung diseases in people, but less is known about the effects of PM2.5 exposure on the brain. Polycyclic aromatic hydrocarbons (PAH) and toxic metals are major components of PM2.5, which are generated during burn pit operation. Many research studies of the effects of PM2.5 and PAH have focused on exposure to males. Since women make up increasing proportions of the Armed Forces, it is important that experimental studies include both males and females. Previous studies have shown that exposure to PM2.5 decreased sperm counts in male mice. Fortunately, these decreases are usually not permanent due to cells in the testicles that can generate new sperm. In contrast, the ovary is not able to generate new eggs once all the eggs are exhausted. Our published data show that 12-week exposure to PM2.5 at levels that meet the current National Ambient Air Quality Standard destroys the irreplaceable ovarian supply of eggs, resulting in a premature menopause-like condition. Premature menopause is known to increase risk for Alzheimer s disease (AD) in women. Objectives: We predict that PM2.5 exposure permanently depletes the ovarian supply of eggs and has reversible effects on sperm production in the testicles. We further predict that PM2.5 exposure will cause inflammation in the brains of both males and females, which could contribute to brain degeneration and AD. We also predict that destruction of eggs in the ovaries caused by exposure to PM2.5 increases Alzheimer s disease progression in females, while males are affected to a lesser degree. In our first aim, we will test the effects of exposure to concentrations of PM2.5 similar to those measured around burn pits on the brains, ovaries, and testicles of normal wild type mice compared to mice that have a genetic modification that makes them more likely to develop brain changes typical of AD. Mice will be exposed when they are in late adolescence. This mimics the ages of many military personnel deployed to Iraq and Afghanistan. We will count the number of eggs in the ovaries in females and count sperm in males. We will do behavioral tests to assess brain function and measure brain inflammation and brain molecules that are changed in AD. These will be measured at the end of the exposure period and again 9 months after the exposure ends (around middle age for a mouse). In our second aim, we will test whether removing the ovaries or testicles worsens the effects of PM2.5 exposure on the brain. We will also test whether supplementing the ovarian hormone estrogen in females from which the ovaries were removed or the testicular hormone testosterone in males from which the testicles were removed protects against these effects of PM2.5 exposure on the brains. Applicability of the Research and How it Addresses Toxic Exposure Research Program Goals: Most basic research studies of AD have utilized mouse or rat models that mimic hereditary, early-onset human AD, but most human AD cases are not hereditary and occur late in life. We will use a mouse model that mimics late-life human AD, so our results will shed light on how PM2.5 exposure from burn pits and other sources contributes to human late-onset AD and how this differs in males and females. The proposal addresses Program Goal 1, Elucidate mechanisms of how toxic exposures, specifically PM2.5 and its constituents, result in adverse effects. It also addresses the Topic Area Neurodegeneration (Focus Areas 1, Understand relationship between toxic exposures and long-term neurologic disorders, specifically the relationship between burn pit exposures and AD; Focus Area 2, Elucidate basic mechan
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311062
Entities
People
- Ulrike Luderer
Organizations
- United States Army
- University of California, Irvine