Where Does Cancer Start?

By Marc Lappé

As one of its first studies, the new Genetic Integrity/Cancer Protection Project at CETOS is focusing on the phenomenon known as “perinatal carcinogenesis,” or the ability of chemical exposure during the time a developing child is in the uterus or nursing to produce cancer. Our work will focus on the special time window between conception and birth as a potential period of exquisite vulnerability to the later development of cancer.

The idea that cancer is a disease of old age hides the fact that many cancers may have their origin decades earlier. Some chemicals, especially those that have hormonal activity, can begin the cancer process in the womb. The experience of the “DES-daughters” is a case in point. DES is the abbreviation for diethylstilbestrol, an estrogen-like synthetic hormone prescribed to over 1 million women between 1950 and 1962 in the mistaken belief that this extra estrogen would overcome their tendency towards miscarriage. In the late 1950s, physicians learned that DES was useless (it actually caused more miscarriages than it prevented) but continued to prescribe it anyway.

Only a decade later did anyone suggest that DES created a cancer risk to those who took it, especially to their offspring. Mothers who took this potent hormone—even as little as 2 mg of it—unknowingly were courting the risk of perinatal carcinogenesis. In 1962 University of Chicago physician Arthur Herbst reported that about 1 in every thousand daughters of women who had taken DES would develop a rare cancer of the junction between the cervix and the uterus when they reached early adulthood. This astonishing finding set the stage for a revolution in drug and chemical safety testing. The lesson of DES appeared to be straightforward—even tiny amounts of extra hormones during pregnancy could produce a delayed effect in exposed offspring. But it was a lesson that few researchers took to heart.

A Brief History of Perinatal Carcinogenesis
In the 1970s, Russian researchers like Sergei Vesselinovitch who is now at the University of Chicago alerted their colleagues to the ability of a wide spectrum of chemical carcinogens to produce cancer following exposure in the uterus. More urgently, these researchers argued that the fetus was especially vulnerable to the gene-damaging effect of cancer causing chemicals, and would be expected to develop many more cancers on a dose-by-dose basis than would others who had not been exposed in utero. For some chemicals, this risk extended into the newborn period when certain enzyme systems that break down chemicals into active carcinogens reach maturity. As a post-doctoral student in 1969, I worked with one of these chemicals, known as urethane. I found that newborn exposure was a potent means of inducing lung cancers later in adulthood.

By 1979, American researchers were sufficiently concerned about the period before birth being a potent time of cancer-initiating events. Many argued for including pre-natal testing of chemicals to find others that behaved like DES as perinatal chemical carcinogens. Almost twenty years elapsed before such testing was introduced. Now, it is commonplace for the National Toxicology Program to include a test for perinatal carcinogenesis in its assays of chemicals for cancer. This testing regime includes giving the chemical before mating and then throughout the pregnancy period, continuing on to nursing. Tests are typically done either uniquely through the perinatal period or in conjunction with later adult exposure. When a perinatal test is included as part of lifetime, adult testing, some carcinogens that are only weakly cancer-causing (or non-cancerous) in adults were found to be potent carcinogens when given to fetuses. An example is the group of chemicals known as polybrominated biphenyls (PBBs) which inadvertently contaminated the feed of dairy cattle in the Midwest in the 1980s and led to the contamination of tens of thousands of Americans who later drank the milk. Of greater interest was the finding (in female rats) that intrauterine exposure to PBBs during pregnancy, followed by adult exposure dramatically enhanced the ability of the chemicals to produce cancer compared to adult exposure alone. This same effect was seen with other chemicals, such as ethylene thiourea which causes an abundance of thyroid cancers if the adult-treated test animals had been exposed during their prenatal life.

The message of these studies, while probably specific for only certain chemicals, is clear. Exposure to carcinogens or radiation before and just after birth can set in motion a series of largely irreversible steps that put the child, and later the adult, at enhanced risk of cancer. For instance, exposure of babies to high amounts of an insulin—like growth hormone (IGF) stimulating substance during their fetal development is directly correlated with birth weight—which in turn is correlated with a later increase in breast cancer risk. Because many products or circumstances can increase (or decrease) the amount of IGF in an infant’s life, most notably the alleged increase in IGF in bovine-somatotropin stimulated dairy cows’ milk, this issue is of prime importance.

What Happens to Our DNA?
A common denominator for radiation and chemical-induced perinatal cancer is the ability of the offending substance to damage DNA, especially in the rapidly dividing cells of the fetus. Certain exposures, such as to chemical carcinogens like those found in cigarette smoke, will produce cancer (such as lung cancer) in adulthood from fetal exposure during during the period of rapid lung development. Other exposures, such as to chemicals in smoked foods or other so-called “N-nitroso” compounds, have been hypothesized to be responsible for some of the increasing numbers of brain cancer in children. Why Children Are More Susceptible than Adults Sometimes “young cells” appear to be more susceptible to cancer causing effects, say from radiation, than are older cells. This phenomenon is vividly demonstrated in dogs exposed to radiation while in the womb to small amounts of Cobalt 60. Over a lifetime, dogs irradiated before birth were dramatically more likely to get fatal cancer than were newborn dogs exposed to approximately the same dosage. Other chemicals, such as anti-oxidants or common drug-enzyme inducing chemicals like Phenobarbital can protect against radiation or chemically induced perinatal carcinogenesis.

The Genetic Integrity Project
Our project is concerned with identifying ways of reducing the DNA-damage from early exposures to hazardous chemicals and thereby protecting children and living organisms. Often protective agents, such as anti-oxidants found in the diet, may prove to be beneficial. Elsewhere, certain chemicals with potent gene-altering ability when exposure occurs before birth may have to be curtailed.

Finally, certain chemicals generally increase the risk of genetic damage through an indirect effect: by depleting a protective enzyme, substrate or environmental chemical that otherwise protects us from genetic damage. A case in point is the present explosive increase in ultraviolet radiation striking the earth and ocean surface as a result of the pollution-driven depletion of the ozone layer. In Argentina and Chile, a dramatic increase in gene damaged plants and animals have been found. In Australia, the current epidemic of skin cancer can probably also be partially attributed to a flux of UV light from ozone depletion. If we are interested in protecting the genetic integrity of species, we of necessity are interested in limiting the chemicals which reduce ozone and thereby increase the amount of DNA-damaging UV light.

We at CETOS hope to forge effective alliances to promote our ideas and program in this new project to preserve genetic integrity and reduce cancer risks accordingly.

References to the above article are included at the article link on our CETOS website: http://www.cetos.org/geneinteg.html