Endocrine disruptors such as dichlorodiphenyltrichloroethane (DDT) have long been recognized as health threats in animal models. But solid data on the effects of DDT and related chemicals in humans has been more elusive. One reason is that some of the deleterious effects of DDT are not seen in individuals exposed to the substance, but in later generations.
“Exposure of a pregnant mother to DDT exposes three generations simultaneously, the mother, her child, and that child’s developing reproductive cells exposed in utero,” said Barbara A. Cohn, PhD, director of the Child Health and Development Studies. “That means, among other things, that observing the course of a single pregnancy gives you three generations of direct data. And errors in the reproductive cells in the third generation may be passed on to the fourth generation without direct exposure.”
Dr. Cohn discussed some of the ways the CHDS is using multiple generations of data during her plenary presentation on “Endocrine Disrupting Chemicals and Multigenerational Health Consequences” on Sunday morning.
The original cohort was approximately 20,000 pregnancies in patients of the Kaiser Permanente Medical Group in Northern California. Successive generations of researchers have followed the original cohort, their children, grandchildren, and great-grandchildren.
In addition to data on each pregnancy, CHDS has health records for the six months prior to pregnancy for each woman in the original cohort as well as data collected during well baby and acute medical visits plus exams at age five, nine to eleven, 15 to 17, 33, 44, and 50. Similar data are being collected for individuals in successive generations, but current research programs are focused on the F1 cohort, the first generation offspring.
The dataset includes more than 65,000 serum samples from 1960 to the present. One of the most striking initial findings was the ubiquitous presence of DDT in the initial cohort. The use of DDT was banned in the United States in 1972.
“There are no women in the F0 cohort who do not show exposure to DDT in blood samples,” Dr. Cohn said. “There are actually three different DDT exposures: the insecticide, its metabolites, and its contaminants. What we have found is that the impact varies by the type of exposure, (insecticide, metabolite, or contaminant), and by the timing of exposure, gestational, peripubertal, or during pregnancy.”
Each of the three forms of DDT has been identified as an endocrine disruptor in animal studies. Earlier studies of women in the F0 cohort found similar evidence of endocrine disruption in the years after DDT was banned and exposure waned as the insecticide, its metabolites, and contaminants began to degrade. More recent studies have found links to breast cancer, reduced fecundability, testicular cancer, increased breast density, DNA methylation, and hypertension in the children of the original cohort.
“The F1s are a spectacular midlife cohort,” Dr. Cohn said. “What makes them so spectacular is that we have in utero data on each of them as well as complete medical histories.”
The odds ratio for breast cancer in the F0 and F1 cohorts is linked to the timing of exposure, Dr. Cohn said. Women who were exposed at four years of age or younger had up to a 12-fold increased risk for breast cancer. The risk of breast cancer decreased with increasing age at exposure, but never disappears. Women in the F1 generation with only in utero exposure still had up to a four-fold increased risk for breast cancer. Increasing in utero exposure is also associated with increased risk for higher breast tissue density.
The effect of time to pregnancy in the F1 generation varied by the type of exposure. In utero exposure to DDT itself resulted in increased fecundity, Dr. Cohn reported. But exposure to DDE, the persistent metabolite of DDT, reduced fecundity and increased time to pregnancy.
Higher exposure to DDT and its metabolites increased the risk for testicular cancer in male offspring, she reported. Greater exposure to DDT and metabolites increased the risk of hypertension in both male and female offspring by the age of 50.
“We are finding and exploring multiple pathways by which DDT might exert its disruptive actions,” Dr. Cohn said. “What we know is that different forms of DDT affect different metabolic pathways and all of them seem to affect lipid metabolism. Targeted animal testing is helping determine the mechanisms involved.”