Papers of the Month
By Sara Amolegbe
Exposure to DES linked to ADHD in grandchildren
Exposure to the drug diethylstilbestrol (DES) may be linked to an increased risk of attention deficit hyperactivity disorder (ADHD) in grandchildren of women who used it, according to an NIEHS study. This is the first study linking DES and a neurodevelopmental outcome that extends to users’ grandchildren.
DES was an endocrine-disrupting chemical prescribed in the U.S. to prevent pregnancy complications. It was banned in 1971 after studies reported negative reproductive outcomes in the daughters of women who used it during pregnancy.
In this study, researchers examined 47,540 participants from the Nurses’ Health Study II, analyzing three generations. Participants and their mothers reported DES use during pregnancy, and physicians diagnosed ADHD in participants’ children.
The odds of having ADHD were 36 percent higher in grandchildren of women who used DES during pregnancy compared with grandchildren of women who did not. The odds of having ADHD jumped to 63 percent if the grandmothers took DES during their first trimester, which suggested that this time period might be a more sensitive exposure window. The association did not change based on the sex of the grandchildren.
Several high production chemicals in commercial products are known or suspected endocrine disruptors. Although humans are exposed to them at much lower levels than the levels at which DES was prescribed, the authors cautioned that cumulative consequences of these endocrine-disrupting chemicals warrant consideration.
Citation: Kioumourtzoglou MA, Coull BA, O'Reilly EJ, Ascherio A, Weisskopf MG. 2018. Association of exposure to diethylstilbestrol during pregnancy with multigenerational neurodevelopmental deficits. JAMA Pediatr 172(7):670–677.
How carcinogens turn liver cells into cancer cells
A new study by NIEHS grantees and colleagues explains how DNA damage to liver cells can potentially lead to liver cancer. The researchers looked at CD44 proteins, which are located on the cell surface and are involved in binding with other molecules. They found that CD44 proteins may play a role in overriding the body’s natural protective response to DNA damage.
The team focused on the most common type of liver cancer — hepatocellular carcinoma (HCC). In mice exposed to toxicants known to induce HCC and in mice more prone to develop HCC, they found increased CD44 expression in precancerous and cancer cells. They also discovered that mice lacking CD44 were less likely to develop HCC.
The researchers explored how CD44 plays a role in HCC by examining its effect on p53, a tumor suppressor protein. p53 is normally activated after DNA damage to stop the damaged cells from dividing. The researchers found that p53 became inactive or was not present 2-3 days after toxicant exposure in mice with CD44. In contrast, mice that lacked CD44 still had active p53 in liver cells several days after exposure. The results indicated that CD44 may be involved in turning off the p53 response to DNA damage, which then allows the cells to continue to divide and accumulate mutations. The accumulation of mutations may lead to development of tumors.
According to the authors, these findings suggest that CD44 inhibitors or compounds that block their interactions in the cell may be potential targets for tumor prevention and therapy.
Citation: Dhar D, Antonucci L, Nakagawa H, Kim JY, Glitzner E, Caruso S, Shalapour S, Yang L, Valasek MA, Lee S, Minnich K, Seki E, Tuckermann J, Sibilia M, Zucman-Rossi J, Karin M. 2018. Liver cancer initiation requires p53 inhibition by CD44-enhanced growth factor signaling. Cancer Cell 33(6):1061–1077.
Computational tool predicts chemical toxicity
NIEHS grantees and colleagues developed a computational tool that uses the properties of a chemical to predict its toxicity. They determined that the tool can predict a toxicity value with an error of less than a factor of 10, making it useful for quickly assessing relative risks of chemicals for which traditional toxicity data or human health assessments are unavailable.
Using a comprehensive database of chemicals with existing regulatory toxicity values from U.S. federal and state agencies, the researchers developed quantitative structure-activity relationship (QSAR) models. The QSAR models use information about known relationships between chemical structures and biological activity to predict the activities of chemicals that do not have existing toxicity values.
The authors compared their QSAR model predictions to those based on high-throughput screening (HTS) assays. HTS assays rapidly measure the potential toxicity of large numbers of chemicals by exposing cells to chemicals and assessing cellular changes. The researchers found that the QSAR model predictions were more accurate and more precise than those based on HTS assays.
According to the authors, this tool can fill a critical gap in the assessment of chemicals without sufficient toxicity data. The researchers have made the tool publicly available on the Conditional Toxicity Value Predictor website, where users can calculate predicted toxicity values for chemicals or retrieve existing toxicity values used to build the QSAR models.
Citation: Wignall JA, Muratov E, Sedykh A, Guyton KZ, Tropsha A, Rusyn I, Chiu WA. 2018. Conditional Toxicity Value (CTV) Predictor: an in silico approach for generating quantitative risk estimates for chemicals. Environ Health Perspect 126(5):057008.
Genetic variation in mothers linked to mercury levels and children’s neurodevelopment
Mothers with certain genetic variations may have different levels of mercury in their hair and their children may have different early neurodevelopmental outcomes, according to an NIEHS-funded study. The researchers focused on how a mother’s genetic differences could influence her levels of mercury and the levels in her children. They also looked at associations between these levels and early life development.
The researchers studied 1,449 mothers in Seychelles who eat a diet rich in fish, which is the main source of low-level mercury exposure in people. They examined associations among mercury levels in maternal hair and blood, mercury in fetal cord blood, and mental and motor development during childhood. They also examined maternal genetic differences, focusing on glutathione (GSH) pathways, which play a key role in the metabolism and elimination of mercury.
They showed that some maternal GSH-related genes were associated with higher levels of mercury concentrations in the mothers’ hair but not in maternal or fetal blood. One maternal genetic difference was also linked to lower mental development among children. The researchers observed that certain GSH-related gene variations in the mother modified the associations between increased mercury levels in hair and blood and mental and motor development in the child.
According to the authors, the results indicate that maternal genetic variation in GSH-related genes potentially influence maternal mercury metabolism, which may affect associations between mercury exposure and developmental outcomes. The findings provide evidence that health impacts of a fish-rich diet during pregnancy may differ among individuals within a population.
Citation: Wahlberg K, Love TM, Pineda D, Engstrom K, Watson GE, Thurston SW, Yeates AJ, Mulhern MS, McSorley EM, Strain JJ, Smith TH, Davidson PW, Shamlaye CF, Myers GJ, Rand MD, van Wijngaarden E, Broberg K. 2018. Maternal polymorphisms in glutathione-related genes are associated with maternal mercury concentrations and early child neurodevelopment in a population with a fish-rich diet. Environ Int 115:142–149.