Papers of the Month
By Adeline Lopez
Common pesticide enhancer linked to rare birth defect in mice
NIEHS grantees found that a chemical commonly used to make pesticides more effective, called piperonyl butoxide (PBO), can cause rare birth defects in the brains and faces of mice exposed in the womb. They examined how PBO exposure can interfere with a signaling pathway called sonic hedgehog (Shh), which is critical for many aspects of early development, including formation of the brain.
To uncover how PBO interferes with normal Shh signaling, the researchers exposed mouse and human cells to PBO and to two other compounds known to result in brain defects, cyclopamine and vismodegib. They also examined how PBO altered normal development by exposing pregnant mice to varying doses of PBO on gestational day 7.75, a critical period for normal brain development.
They reported that PBO inhibited Shh signaling in both mouse and human cells through a mechanism similar to that of cyclopamine, a known developmental toxin. However, PBO was found to be four times less potent. In fetal mice, the highest PBO exposure severely stunted forebrain development and caused facial abnormalities similar to a severe condition known as holoprosencephaly in humans. Lower doses of PBO disrupted forebrain development in more subtle ways that might be linked to altered neurodevelopment or behavior.
By focusing on changes to Shh signaling, the authors defined a lowest observable effect level ― more than 30 times lower than previously recognized for PBO developmental toxicity in mice. According to the authors, the results demonstrated that preventing PBO exposures in pregnant women might be important to protecting children’s neurodevelopment.
Citation: Everson JL, Sun MR, Fink DM, Heyne GW, Melberg CG, Nelson KF, Doroodchi P, Colopy LJ, Ulschmid CM, Martin AA, McLaughlin MT, Lipinski RJ. 2019. Developmental toxicity assessment of piperonyl butoxide exposure targeting sonic hedgehog signaling and forebrain and face morphogenesis in the mouse: an in vitro and in vivo study. Environ Health Perspect 127(10):107006.
Sensor uses carbon nanotubes to detect airborne nitrosamines
NIEHS grantees recently developed a sensitive, inexpensive sensor that uses carbon nanotubes to measure airborne N-nitrosamines in real time. N-nitrosamines are toxic by-products formed during manufacturing and food processing and have been found in air, water, and food. Before the development of this tool, detecting N-nitrosamines was a long, expensive, and technically challenging process.
The researchers developed the sensor, evaluated its performance, and explored different parameters to optimize the device for detecting relevant levels of N-nitrosamines, including N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosodibutylamine (NDBA).
The final product consisted of functionalized cobalt (III) tetraphenylporphyrin molecules deposited onto single-walled carbon nanotubes. The carbon nanotubes were stretched between gold electrodes, which conducted current through the nanotubes. The cobalt (III) tetraphenylporphyrin molecules selectively bound to N-nitrosamine compounds in air, which resulted in a change in electrical resistance across the electrodes. Researchers can measure the change to determine the concentration of N-nitrosamines.
The researchers demonstrated that the small, portable sensors could detect concentrations of NDMA, NDEA, and NDBA as low as 1 part per billion without background interference. They also showed that the sensor could be integrated with a commercial sensing chip device so results can be monitored remotely using a computer or smartphone.
Citation: He M, Croy RG, Essigmann JM, Swager TM. 2019. Chemiresistive carbon nanotube sensors for N-nitrosodialkylamines. ACS Sens 4(10):2819–2824.
Early prenatal exposure to endocrine disruptors linked to lower IQ
Exposure to a mixture of suspected endocrine-disrupting chemicals (EDCs) early in pregnancy may reduce IQ in children, according to a new NIEHS-funded study. EDCs are chemicals that can interfere with hormone action, even at low levels. This is the first study to investigate prenatal exposure to suspected EDC mixtures in relation to child neurodevelopment.
The researchers analyzed blood and urine samples from 718 mothers participating in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study. Samples were taken during the women’s first prenatal visit to the clinic. The team assessed the relationship between 26 EDCs in the mother’s blood and urine and her child’s IQ, measured at age 7 years. They adjusted their models for the child’s sex, gestational age, and the mother’s education, IQ, weight, and smoking status.
They found that early prenatal exposure to the EDC mixture was associated with lower IQ in children, and that the EDC mixture disproportionately affected boys. The researchers estimated that boys in the highest quarter of exposure levels had IQ scores that were approximately 2 points lower than boys in the lowest quarter of exposure levels. Within the mixture, the team identified specific chemicals that most highly contributed to a lower IQ. Bisphenol F (BPF), a bisphenol A (BPA)−replacement compound, made the largest contribution, followed by a pyrethroid pesticide, an organophosphate pesticide, two phthalates, three per- and polyfluoroalkyl substances, triclosan, and BPA.
According to the authors, identification of BPF as the primary chemical of concern suggests that the BPA replacement may not be safer for children.
Citation: Tanner EM, Hallerback MU, Wistrom S, Lindh C, Kiviranta H, Gennings C, Bornehag CG. 2019. Early prenatal exposure to suspected endocrine disruptor mixtures is associated with lower IQ at age seven. Environ Int 19:105185.
Daily cycles in harmful algal blooms
An NIEHS-funded study shed light on harmful algal bloom (HAB) changes during different times of day. HABs occur when toxin-producing algae grow excessively in a body of water. Environmental factors such as light, temperature, and nutrient levels can play a role in production of toxins that can seriously harm people, fish, and other parts of the ecosystem.
The researchers collected samples from a toxic Microcystis cyanobacteria bloom in Lake Erie in 6-hour intervals over a 48-hour period and analyzed DNA to determine which genes were active during different parts of the day. Specifically, they looked at genes involved in metabolic functions, such as photosynthesis, nutrient uptake, cell division, and toxin production.
They found that patterns suggesting that genes related to cell division and acquisition of nitrogen, a critical nutrient for growth, were most active during the day. Similarly, genes related to stress response, such as temperature, had increased expression during the day. In contrast, genes expressed during the night were associated with carbon fixation, in which plants can convert inorganic carbon to sugar for energy, and phycobilisome protein synthesis, which allows algae to use wavelengths of light much deeper in the water column.
According to the authors, these findings explain differences in how genes are expressed during different times of the day and may help inform strategies to predict HABs and mitigate these events.
Citation: Davenport EJ, Neudeck MJ, Matson PG, Bullerjahn GS, Davis TW, Wilhelm SW, Denney MK, Krausfeldt LE, Stough JMA, Meyer KA, Dick GJ, Johengen TH, Lindquist E, Tringe SG, McKay RML. 2019. Metatranscriptomic analyses of diel metabolic functions during a microcystis bloom in western Lake Erie (United States). Front Microbiol 10:2081.