Papers of the Month
By Megan Avakian
Promising therapy for fatal sickle cell disease complication
An NIEHS-funded study in mice showed how chlorine exposure leads to Acute Chest Syndrome (ACS), a leading cause of death in patients with sickle cell disease (SCD). The results point to a potential lifesaving therapy for SCD patients exposed to chlorine. Chlorine is found in some household cleaning products and is commonly encountered in industrial accidents and chemical warfare.
SCD is a group of blood disorders in which the hemoglobin protein is defective, causing red blood cells (RBCs) to rupture. The researchers used genetically engineered mice that resembled SCD in humans (sickle mice) and compared them to healthy control mice with human hemoglobin. They exposed both groups to chlorine gas or normal air and assessed survival, lung injury, and hemolysis, or the rupture of RBCs which releases hemoglobin into the blood. They repeated this process but injected mice with hemopexin, which binds to hemoglobin.
Within six hours of chlorine exposure, 64 percent of sickle mice died while none of the controls died. Compared to controls, surviving sickle mice had hemolysis and lung injury. Hemolysis resulted in increased blood levels of heme, a component of hemoglobin known to cause lung injury. Hemopexin treatment following exposure significantly improved survival and reduced blood heme levels and lung injury. RBCs from chlorine-exposed sickle mice had high carbonylation, which increases cell rupture. Carbonylation was absent after hemopexin treatment.
According to the authors, results indicate that chlorine exposure induces ACS-like outcomes in sickle mice and that hemopexin treatment after exposure reduces death and lung injury.
Citation: Alishlash AS, Sapkota M, Ahmad I, Maclin K, Ahmed NA, Molyvdas A, Doran S, Albert CJ, Aggarwal S, Ford DA, Ambalavanan N, Jilling T, Matalon S. 2021. Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin. Redox Biol 44:102009.
Higher temperatures linked to lower ovarian reserve
Women exposed to higher temperatures had a lower ovarian reserve, found NIEHS-funded researchers. Ovarian reserve refers to the number and quality of a woman’s eggs. A diminished ovarian reserve reduces a woman’s ability to get pregnant.
The study included 631 women aged 18-45 years enrolled in a reproductive health study in Massachusetts. Using each woman’s home address, the researchers estimated daily ambient temperature exposures for three months, one month, and two weeks before the ovarian reserve examination. They used ultrasonography to measure antral follicle count (AFC), a measure of ovarian reserve.
Exposure to higher temperatures was associated with a lower AFC. Specifically, a 1-degree Celsius increase in average maximum temperature three months before ovarian reserve testing was associated with a 1.6 percent lower AFC. This relationship remained negative but weakened for one month and two weeks before AFC testing. The negative association between temperature and AFC was stronger in November through June compared to the summer months. According to the researchers, this suggests that women may be more susceptible to heat during certain times of the year, potentially because they adapt to heat in the summer.
Study findings raise concerns that the steady increase in global temperature due to climate change may result in accelerated reproductive aging in women, say the researchers.
Citation: Gaskins AJ, Minguez-Alarcon L, VoPham T, Hart JE, Chavarro JE, Schwartz J, Souter I, Laden F. 2021. Impact of ambient temperature on ovarian reserve. Fertil Steril; doi: 10.1016/j.fertnstert.2021.05.091. [Online 8 June 2021]
Gene atlas provides insight into breast cancer origin
NIEHS grantees developed a gene expression atlas that captures the cellular makeup of the mammary gland across life stages, providing clues to how breast cancer originates. The female breast is made up of different cell types and undergoes reorganization during development, pregnancy, and menopause, increasing breast cancer risk.
To build the atlas, the researchers used single cell RNA sequencing data, which assesses gene and protein expression of an individual cell. They integrated data from 50,000 mouse mammary cells covering eight life stages and 24,000 adult human mammary cells.
The data formed three clusters. Using known genetic markers, they identified the clusters as three breast epithelial cell types. Connecting the clusters were embryonic mammary stem cells, which can give rise to each epithelial cell type. Advanced computational methods suggested the breast epithelium originated from embryonic mammary stem cells that differentiated into epithelial cells through postnatal progenitor cells.
The researchers compared genetic profiles for each epithelial cell type with known cancer-related genes to infer breast cancer cells of origin. This can help pinpoint tumor origin since cancer often starts from a single transformed cell. They also examined how reorganization during different life stages altered breast cellular makeup and breast cancer subtype risk. For example, during pregnancy the breast had increased basal epithelial cells, potentially increasing risk of the basal breast cancer subtype. According to the authors, the atlas provides insights into cellular makeup and development of breast cancer subtypes.
Citation: Saeki K, Chang G, Kanaya N, Wu X, Wang J, Bernal L, Ha D, Neuhausen SL, Chen S. 2021. Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis. Commun Biol 4(1):660.
Placental genes transfer effects of maternal air pollution exposure to the developing fetus
The placenta may play a critical role in conveying the effects of particulate matter air pollution (PM2.5) exposure during pregnancy to the developing fetus, according to a new NIEHS-funded study. The researchers found that maternal PM2.5 exposure during certain periods of pregnancy leads to reduced fetal growth, especially in females.
The study included 840 women and their children enrolled in a birth cohort study in Rhode Island between 2009-2013. Using spatiotemporal models and the women’s home addresses, the researchers estimated maternal weekly PM2.5 exposure from 12 weeks preconception until birth. They overlaid a previously developed placental gene network with PM2.5 exposure data to identify genes associated with air pollution exposure. They used gestational age and birth weight collected at birth to assess fetal growth.
The researchers identified a sensitive window spanning 12 weeks prior to and 13 weeks into pregnancy during which higher maternal PM2.5 exposure was associated with significantly lower infant birthweight and shorter gestational age across all timepoints. Female infants were particularly vulnerable to PM2.5-induced deficits in fetal growth. Disruption of placental genes important in amino acid transport and cellular respiration were correlated with maternal PM2.5 exposure and infant birthweight, suggesting that the placenta conveyed air pollution-related impacts to the developing fetus.
According to the authors, results suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects.
Citation: Deyssenroth MA, Rosa MJ, Eliot MN, Kelsey KT, Kloog I, Schwartz JD, Wellenius GA, Peng S, Hao K, Marsit CJ, Chen J. 2021. Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight. Environ Res 199:111342.
(Megan Avakian is a science writer for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)