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Research Newsletter-Spring/Summer 2011

Lyndsey Shorey

PROTECTING THE FETUS FROM CARCINOGENS



Lyndsey Shorey
LPI Graduate Fellow


Summary: Feeding indole-3-carbinol (I3C), a phytochemical found in cruciferous vegetables, to pregnant mice can protect against cancer in the offspring from in utero exposure to chemical carcinogens. In the body, I3C reacts to form another compound, diindolylmethane (DIM). Human leukemia cells in culture treated with DIM exhibited depressed growth and increased apoptosis (programmed cell death), which is beneficial for cancer protection.

In 1997 a panel of scientists from the World Cancer Research Fund and the American Institute for Cancer Research estimated that 30-40% of all cancers could be prevented by modifying lifestyle factors like diet and exercise. Ten years later, the panel reported only a "probable" protective effect of fruits and vegetables on cancer risk. While vegetables are generally known to be healthful, as they are high in fiber, vitamins, and minerals, and low in fat and cholesterol, it has been difficult to demonstrate a direct association between overall vegetable consumption and cancer prevention in humans due to the heterogeneity of exposures, genetics, and, ultimately, the diseases collectively referred to as cancer. However, certain types of vegetables produce phytochemicals that are not essential nutrients but may have beneficial health properties.

Broccoli, Brussels sprouts, mustard, kale, cabbage, horseradish, and arugula are in the Cruciferae plant family and are a rich source of a class of phytochemicals known as glucosinolates. Glucosinolates are sulfur-containing compounds that contribute to the sometimes bitter or pungent aroma and flavor of these vegetables. In order for glucosinolates to become biologically active, they must be metabolized by myrosinase—a plant enzyme released from the plant tissue when it's chopped or chewed—into two classes of chemicals known as indoles and isothiocyanates, which are widely accepted as responsible for the beneficial health properties of crucifers. Over 100 different glucosinolates have been identified, and when acted upon by myrosinase, they yield unique products. Some glucosinolates are found in all cruciferous vegetables, and others may be especially enriched in particular vegetables. For example, indole-3-carbinol (I3C) is derived from the glucosinolate glucobrassicin, abundant in broccoli, Brussels sprouts, kale, and cabbage. Interest in isothiocyanates as anticancer agents has been growing since the 1960s, and sulforaphane (SFN), derived from another glucosinolate (glucoraphanin), abundant in broccoli and broccoli sprouts, has become the most studied isothiocyanate.

Conversion of glucobrassicin in food to diindolylmethane in the stomach.

Previously, our lab utilized a transplacental mouse model to look specifically at the ability of maternal diet to alter cancer risk in offspring exposed to chemicals in utero and/or through lactation. Women are unavoidably exposed to environmental pollutants during pregnancy, and the fetus is especially sensitive to these chemicals. One class of chemicals known as polycyclic aromatic hydrocarbons (PAHs) are produced from the combustion of fossil fuels and released into the air we breathe and the soil in which our food grows. If pregnant mice are exposed only once to the PAH dibenzo[def,p]chrysene (DBC), their offspring succumb to T-cell lymphoblastic lymphomas during early adulthood and lung tumors later in life. We have used this model to demonstrate significant protection against DBC-induced lung tumors and T-cell lymphomas in offspring when the maternal diet is supplemented with 2,000 parts per million (ppm) I3C.

Multiple mechanisms exist for the anti-carcinogenic actions of indoles and isothiocyanates. These mechanisms are broadly classified as either blocking or suppressive, based on the respective phases, known as initiation and progression, of cancer development during which these mechanisms are effective. Before the anticancer effects of these phytochemicals were known, their ability to modulate metabolism and detoxication of foreign substances in the body had been identified. Indoles and isothiocyanates are considered blocking agents, as they are capable of altering the rate and extent to which a person, tissue, or cell can eliminate certain carcinogens. Furthermore, these compounds can be effective in reducing the progression of cancer cells by targeting what are known as cancer survival pathways. Normal cells have intrinsic sensors that are encoded by our DNA and prevent them from dividing when an error in the replication machinery occurs. When a cell is exposed to certain carcinogens, resultant mutations in its DNA may change the code so that these sensors are damaged or deleted, resulting in uncontrolled regulation of cell growth and activation of the survival pathways, leading to cancer.

My work has primarily focused on the suppressive mechanisms of I3C on human cancer cells from a patient with T-cell leukemia. I3C is highly unstable; when it enters an acidic environment, such as the stomach, two or more I3C molecules readily link together to form what is known as an acid condensation product. The primary product of this reaction is the dimer diindolylmethane (DIM). In rodents and humans consuming I3C, very little I3C is measurable in plasma or urine. Therefore, DIM, which is detectable in plasma, is thought to contribute greatly to some of the effects attributed to I3C.

We treated leukemia cells with I3C or DIM and found that many of the same molecular targets were altered by either of the treatments, but DIM was 8-9 times more potent than I3C. Our studies are the first to use DIM in leukemia cells, and our results are consistent with reports in other cancer cells that DIM and/or I3C block the division and proliferation of cancer cells and induce programmed cell death by modulating specific cellular proteins that regulate these processes. Dietary supplementation with DIM also reduced the growth of these human leukemia cells transplanted into mice. Therefore, our data support the current theory that DIM may mediate the physiological effects of I3C.

Cruciferous vegetables have great potential to reduce the risk of certain cancers. Epidemiological studies have suggested an inverse relationship between cruciferous vegetable consumption and gastric, endometrial, and colorectal cancer and cancers of the lung, prostate, breast, and bladder. One explanation as to why these studies have been more suggestive than definitive may be genetic differences in how individuals metabolize these compounds—some of us need to consume more cruciferous vegetables in order to receive the same level of protection. Cooking and storage processes, such as chopping, pickling, freezing, stir-frying, or microwave cooking, also variably influence the amount of glucosinolates in the edible portion of these vegetables. Therefore, it is often difficult to demonstrate the potential health benefits of a particular food when looking at highly heterogeneous human data compared to controlled laboratory studies.

Food Source

The concept that the fetal and early postnatal environment may program the developing individual to have altered susceptibility to disease in adulthood is an exciting and growing field of research termed "fetal origins." Currently, we are using the transplacental model to study whether the whole foods from which I3C, DIM, and SFN are derived can also reduce the cancer risk of offspring exposed to carcinogens in utero. We are supplementing the diet of pregnant mice with broccoli sprouts, Brussels sprouts, I3C, SFN, or the combination of I3C and SFN, and we will monitor the offspring for up to 10 months of age (middle age in a mouse). This study will assess the molecular changes that occur during the development of the lymphomas and lung tumors and the amelioration of these changes by either the active phytochemicals or the whole foods. We will specifically explore epigenetic mechanisms—processes that result in heritable changes in regulation of genes not involving modification of the DNA sequence—as they relate to the fetal origins of cancer.


Last updated July 2011