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Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance.

ABSTRACT: Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early-life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.

SUBMITTER: Cook JD

PROVIDER: S-EPMC1150843 | biostudies-other | 2005 Jun

REPOSITORIES: biostudies-other

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Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance.

Cook Jennifer D JD Davis Barbara J BJ Cai Sheng-Li SL Barrett J Carl JC Conti Claudio J CJ Walker Cheryl Lyn CL

Proceedings of the National Academy of Sciences of the United States of America 20050603 24

Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line de ...[more]

PMID: 15937110

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Project description:PURPOSE:The Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project is a mother-child pregnancy and birth cohort originally initiated in the mid-1990s to explore: (1) whether enhanced mobilisation of lead from maternal bone stores during pregnancy poses a risk to fetal and subsequent offspring neurodevelopment; and (2) whether maternal calcium supplementation during pregnancy and lactation can suppress bone lead mobilisation and mitigate the adverse effects of lead exposure on offspring health and development. Through utilisation of carefully archived biospecimens to measure other prenatal exposures, banking of DNA and rigorous measurement of a diverse array of outcomes, ELEMENT has since evolved into a major resource for research on early life exposures and developmental outcomes. PARTICIPANTS:n=1643 mother-child pairs sequentially recruited (between 1994 and 2003) during pregnancy or at delivery from maternity hospitals in Mexico City, Mexico. FINDINGS TO DATE:Maternal bone (eg, patella, tibia) is an endogenous source for fetal lead exposure due to mobilisation of stored lead into circulation during pregnancy and lactation, leading to increased risk of miscarriage, low birth weight and smaller head circumference, and transfer of lead into breastmilk. Daily supplementation with 1200 mg of elemental calcium during pregnancy and lactation reduces lead resorption from maternal bone and thereby, levels of circulating lead. Beyond perinatal outcomes, early life exposure to lead is associated with neurocognitive deficits, behavioural disorders, higher blood pressure and lower weight in offspring during childhood. Some of these relationships were modified by dietary factors; genetic polymorphisms specific for iron, folate and lipid metabolism; and timing of exposure. Research has also expanded to include findings published on other toxicants such as those associated with personal care products and plastics (eg, phthalates, bisphenol A), other metals (eg, mercury, manganese, cadmium), pesticides (organophosphates) and fluoride; other biomarkers (eg, toxicant levels in plasma, hair and teeth); other outcomes (eg, sexual maturation, metabolic syndrome, dental caries); and identification of novel mechanisms via epigenetic and metabolomics profiling. FUTURE PLANS:As the ELEMENT mothers and children age, we plan to (1) continue studying the long-term consequences of toxicant exposure during the perinatal period on adolescent and young adult outcomes as well as outcomes related to the original ELEMENT mothers, such as their metabolic and bone health during perimenopause; and (2) follow the third generation of participants (children of the children) to study intergenerational effects of in utero exposures. TRIAL REGISTRATION NUMBER:NCT00558623.

Dataset Information

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance.

Publications

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance.

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