Prenatal stress enhances NNK-induced lung tumors in A/J mice

Abstract

Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.

Animal Models of Prenatal Stress

“…Additionally, prenatally stressed mice have significantly increased the number of lung proliferations and area of lesions microscopically compared to the control mice 10) . Immunohistochemically, CD3-positive T cells and Foxp3-positive T cells were evaluated and prenatally stress exposed adult mice had significantly more CD3positive T cells within lung lesions 10) . It is suggested that prenatal stress induces not only early carcinogenesis in offspring but also changes in the tumor immune microenvironment.…”

“…It has been proposed that maternal stress during pregnancy has been linked to cancer in offspring, such as colon cancer and leukemia 3) . In the animal model of lung cancer (A/J mouse), offspring in the prenatal stress group had more proliferative lesions in lung macroscopically compared to offspring in control 10) . Additionally, prenatally stressed mice have significantly increased the number of lung proliferations and area of lesions microscopically compared to the control mice 10) .…”

“…In the animal model of lung cancer (A/J mouse), offspring in the prenatal stress group had more proliferative lesions in lung macroscopically compared to offspring in control 10) . Additionally, prenatally stressed mice have significantly increased the number of lung proliferations and area of lesions microscopically compared to the control mice 10) . Immunohistochemically, CD3-positive T cells and Foxp3-positive T cells were evaluated and prenatally stress exposed adult mice had significantly more CD3positive T cells within lung lesions 10) .…”

“…Previously, there were no animal models to study the influence of in utero maternal stress on reproductive cancer or any other type of cancers 10) . Further study of animal models of prenatal stress is necessary to understand the hormonal effect between mother and fetus, and the mechanism of carcinogenesis.…”

“…A/J mouse has a high spontaneous lung adenoma or adenocarcinoma tumorigenesis that occurs after exposure to the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) 9) 10) . The spontaneous tumorigenesis with A/J mouse is not high but can reach 90% by 18 months 10) .…”