oa Induction of Germ-cell Mutations by Particulate Air Pollutants

The particulate component of urban air pollution contains many compounds that are genotoxic and carcinogenic. Anthropogenic particulates are primarily derived from vehicle and power plant emissions, and various industrial sources. Particulates contain polycyclic aromatic compounds and metals that are known to be either directly or indirectly mutagenic through the creation of DNA adducts and oxidative stress. Although the regulation of acceptable levels of exposure to air pollution are primarily based on cardiopulmonary effects, data from our lab suggest that germ cells are a highly sensitive cell type that are responsive to low levels of particulate air pollution exposure. DNA damage in germ cells can lead to heritable mutations that may result in a wide variety of detrimental outcomes, from embryonic lethality to genetic disease in the offspring. Thus, hazards to germ cells are critically important to evaluate in the context of the health of future generations. Work in our laboratory examines the genetic and epigenetic consequences of parental exposure to particulate air pollutants on their gametes and their unexposed descendants. Our work applies highly unstable repetitive elements in the genome to measure induced mutation in pedigrees or sperm samples of mice. These studies have demonstrated that exposure to various sources of particulate air pollutants cause DNA mutations at repetitive sites in the germline that are inherited. Exposure of male mice to air pollutants leads to increased DNA strand breaks, DNA mutations and altered DNA methylation in sperm. Exposure of male in utero to diesel exhaust particles causes an increase in inherited mutation in their unexposed descendants. Mice exposed to both mainstream and sidestream tobacco smoke at environmentally relevant levels show similar increases in mutation frequency, above those doses leading to induction of somatic mutation. The data demonstrate that particles derived from combustion cause mutation in gametes, possibly mediated by epigenetic events. The mechanisms linking particle exposure and inherited mutation remain elusive but are the subject of research in our laboratory.