Papers of the Month
By Sara Amolegbe
Structure of DNA lesions may affect repair of DNA
NIEHS grantees and colleagues have discovered how proteins involved in the nucleotide excision repair (NER) DNA repair process identify DNA lesions, or structural damage, for removal. The findings provide evidence as to why some lesions triggered by environmental and other agents get repaired, while others remain and may lead to mutations and cancer.
DNA repair begins when the xeroderma pigmentosum C protein complex (XPC) patrols the genome for certain types of DNA lesions. Upon encountering damaged DNA, it inserts a simple protein structure shaped like a hairpin between the two DNA strands so NER proteins can recognize the lesion and remove it. In this study, the researchers described the molecular pathway that Rad4, a yeast version of XPC, takes when it binds to DNA lesions that occur from exposure to benzo[a]pyrene, a combustion byproduct in tobacco smoke and coal tar.
Using a supercomputer, researchers simulated the lesion recognition pathway at an atomic level and found that the structure of the DNA lesion can affect how it is recognized by XPC. For XPC to initially insert the hairpin-like structure, the lesion must contain an extruded and flipped cytosine, one of the four bases found in DNA. They also found that the repair process for benzo[a]pyrene lesions differed significantly from that of a ultraviolet light–induced lesion.
According to the authors, these findings may explain why some people are more vulnerable to DNA damage from certain chemicals and may inform the design of chemotherapeutic drugs that target DNA in cancer cells.
Mu H, Geacintov NE, Min JH1, Zhang Y, Broyde S. 2017. Nucleotide excision repair lesion-recognition protein Rad4 captures a pre-flipped partner base in a benzo[a]pyrene-derived DNA lesion: how structure impacts the binding pathway. Chem Res Toxicol 30(6):1344-1354.
Two insecticides associated with reduced motor skills in infants
A study, funded in part by the NIEHS, has linked the insecticides naled and chlorpyrifos to reduced motor skills in babies. This work is one of the first non-occupational studies on the potential health effects of naled, which is being sprayed in the U.S. to combat the mosquito that transmits the Zika virus.
The researchers examined the umbilical cord blood of approximately 240 mothers in China, looking for exposure to 30 different insecticides, five of which showed up in at least 10 percent of the samples. At 6 weeks and 9 months, they tested the motor skills of the babies using the Peabody Developmental Motor Skill Assessment.
At 9 months, infants in the top 25 percent of naled exposure, compared with those in the lowest 25 percent of exposure, exhibited 3 to 4 percent lower fine motor skills, or the small movements of hands, fingers, face, mouth, and feet. Infants exposed to chlorpyrifos scored 2 to7 percent lower on a range of key motor skills, including large movements of arms and legs and fine motor skills. Girls appeared to be more sensitive to the negative effects of the insecticides than boys. The scientists did not identify significant deficits at 6 weeks.
The researchers said that motor delays in infancy may lead to developmental and cognitive problems later in childhood, and that the new results warrant further exploration of the effects of commonly used insecticides on motor development.
Silver MK, Shao J, Zhu B, Chen M, Xia Y, Kaciroti N, Lozoff B, Meeker JD. 2017. Prenatal naled and chlorpyrifos exposure is associated with deficits in infant motor function in a cohort of Chinese infants. Environ Int; doi:10.1016/j.envint.2017.05.015 [Online 6 June 2017].
Airborne PCBs in urban and rural U.S. schools
An NIEHS-funded study showed that polychlorinated biphenyls (PCBs) are present in older schools and that the likely source is outdated building materials, including window caulking and light ballasts. The multi-year study is one of the largest to examine airborne PCBs in schools.
Though none of the schools had PCB levels high enough to meet federal standards for immediate remediation, researchers found that exposure of school-aged children to PCBs by inhalation may be equal to or higher than exposure through diet.
The researchers collected indoor and outdoor air samples at six schools in Iowa and Indiana from 2012 to 2015. For the first time, they also measured hydroxylated PCB, a PCB metabolite. While PCB levels varied at each school and even within each classroom, the rates of childhood exposure were roughly the same in rural and urban areas. Concentrations inside schools were one to two orders of magnitude higher than concentrations outdoors.
PCBs were used for decades in many industrial applications, such as electrical equipment. Although their manufacture and use are now banned in the U.S., PCBs break down slowly and can remain in the environment for many years. According to the authors, reducing airborne PCBs in older schools may be accomplished by removing old caulk around windows and modernizing light fixtures.
Marek RF, Thorne PS1, Herkert NJ, Awad AM, Hornbuckle KC. 2017. Airborne PCBs and OH-PCBs inside and outside urban and rural U.S. schools. Environ Sci Technol 51(14):7853–7860.
Common disinfectants linked to neural tube defects in rodents
Researchers supported in part by NIEHS found an association between exposure to common household cleaners, called quaternary ammonium compounds, or quats, and neural tube defects in both mice and rats. Neural tube defects are birth defects of the brain or spinal cord.
Male and female mice were exposed to two types of quats — alkyl dimethyl benzyl ammonium chloride and didecyl dimethyl ammonium chloride — which are commonly used in homes, hospitals, and industrial settings. The exposed mice had pups with significantly higher rates of birth defects than unexposed mice. The researchers observed an increased rate of birth defects for two generations after they ended the exposure.
They also found an increase in neural tube defects after only the father was exposed. Male or female exposure that ended 7 to 10 days before breeding led to an increased rate of neural tube defects.
In addition to seeing an effect after rodents were dosed with quats, the researchers found that just using the disinfectants in the same room as the mice led to a 15 percent increase in neural tube defects. With increased human exposure and a scarcity of human data, combined with these observations, the researchers emphasized the need for more studies to evaluate the effects of quats on human health and development.
Hrubec TC, Melin VE, Shea CS, Ferguson EE, Garafola C, Repine CM, Chapman TW, Patel HR, Razvi RM, Sugrue JE, Potineni H, Magnin-Bissel G, Hunt PA. 2017. Ambient and dosed exposure to quaternary ammonium disinfectants causes neural tube defects in rodents. Birth Defects Res; doi: 10.1002/bdr2.1064 [Online 15 June 2017].
(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)