In Utero Exposure to Benzo[a]pyrene Induces Ovarian Mutations at Doses that Deplete Ovarian Follicles in Mice
- DOI
- Language of the publication
- English
- Date
- 2018-10-24
- Type
- Article
- Author(s)
- Luderer, Ulrike
- Meier, Matthew J.
- Lawson, Gregory W.
- Beal, Marc A.
- Yauk, Carole L.
- Marchetti, Francesco
- Publisher
- Wiley
Abstract
Polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) are ubiquitous environmental contaminants formed during incomplete combustion of organic materials. Our prior work showed that transplacental exposure to BaP depletes ovarian follicles and increases prevalence of epithelial ovarian tumors later in life. We used the MutaMouse transgenic rodent model to address the hypothesis that ovarian mutations play a role in tumorigenesis caused by prenatal exposure to BaP. Pregnant MutaMouse females were treated with 0, 10, 20, or 40 mg/(kg day) BaP orally on gestational days 7–16, covering critical windows of ovarian development. Female offspring were euthanized at 10 weeks of age; some ovaries with oviducts were processed for follicle counting; other ovaries/oviducts and bone marrow were processed for determination of lacZ mutant frequency (MF). Mutant plaques were pooled within dose groups and sequenced to determine the mutation spectrum. BaP exposure caused highly significant dose-related decreases in ovarian follicles and increases in ovarian/oviductal and bone marrow mutant frequencies at all doses. Absence of follicles, cell packets, and epithelial tubular structures were observed with 20 and 40 mg/(kg day) BaP. Depletion of ovarian germ cells was inversely associated with ovarian MF. BaP induced primarily G > T and G > C transversions and deletions in ovaries/oviducts and bone marrow cells and produced a mutation signature highly consistent with that of tobacco smoking in human cancers. Overall, our results show that prenatal BaP exposure significantly depletes ovarian germ cells, causes histopathological abnormalities, and increases the burden of ovarian/oviductal mutations, which may be involved in pathogenesis of epithelial ovarian tumors.
Plain language summary
Health Canada is responsible for assessing and managing health risks to Canadians associated with exposure to environmental chemicals. In humans, during development in the womb, the fetus is known to be particularly sensitive to risks posed by environmental chemicals. Such exposures may produce lasting adverse health effects in the offspring of mothers exposed during their pregnancy, including genetic changes resulting in susceptibility to cancer or other genetic diseases. In a previous study, Health Canada used a well-characterized chemical carcinogen, benzo[a]pyrene (BaP), to show that exposure during pregnancy resulted in increases in mutations (changes in the DNA sequence that are associated with genetic diseases such as cancer) in the brain, liver, bone marrow, and sperm of adult male mice. In the present study, Health Canada researchers now report that in utero exposure to BaP is associated with a dramatic reduction in the number of ovarian follicles (the structures that contain the eggs that a female will ovulate during her reproductive life) in the ovaries of adult females. Furthermore, the reduction in follicle numbers was associated with an increase in mutations in the ovary as a whole and with the presence of pathological lesions that have been associated with the development of ovarian cancer in women. These findings suggest that exposure to environmental chemicals during pregnancy may have permanent detrimental effects on the reproductive capacity of females during their adult life and pose them at a higher risk of adverse health effects associated with the induction of mutations in other tissues. Nevertheless, the implications of these findings for human reproduction require further work. These results will be used to improve our knowledge regarding the risk assessment for chemicals.
Subject
- Health,
- Health and safety