Papers of the Month
By Janelle Weaver
Study shows how cadmium affects heart development
2D and 3D model systems provide valuable insights into cellular events and molecular mechanisms associated with cadmium-induced congenital heart disease, according to researchers from the NIEHS Division of Translational Toxicology.
Maternal exposure to cadmium is a significant risk factor for congenital heart disease. But the cellular and molecular mechanisms by which cadmium affects heart development in humans are not well defined, in part due to the lack of appropriate in vitro models.
To address this knowledge gap, the researchers evaluated the effects of cadmium on the different stages of cardiac development. They used an in vitro model of early embryo development as well as a 2D model of heart muscle cell differentiation and a 3D cardiac organoid model that resembles early human fetal hearts.
The results showed that cadmium exposure inhibited the ability of human embryonic stem cells to develop into mature heart muscle cells. This, in turn, impaired cardiac organoid contractions. In addition, the results revealed an early window of sensitivity during heart development, which could mean a possibly lower risk associated with later cadmium exposure.
Together, these findings provided valuable insights into cadmium-induced congenital heart disease and cardiovascular disease. Moreover, the study established a platform for investigating cardiac function and for high-throughput screening of environmental toxicants that could affect heart development.
Citation: Wu X, Chen Y, Luz A, Hu G, Tokar EJ. 2022. Cardiac development in the presence of cadmium: an in vitro study using human embryonic stem cells and cardiac organoids. Environ Health Perspect 130(11):117002.
Immune cell populations may shift before a diagnosis of high blood pressure
Women who develop high blood pressure have altered proportions of immune cells called leukocytes years prior to clinical diagnosis, according to NIEHS researchers and their collaborators.
Chronically high blood pressure, or hypertension, is a risk factor for kidney disease, heart disease, and stroke. Extensive experimental data from animal models suggest that alterations in individual leukocyte subsets may play an important role in the development of hypertension, but the involvement of these cells has not been well examined in large human studies.
To address this knowledge gap, the researchers used biospecimens and health data from 4,124 women, focusing their analysis on 12 different leukocyte subsets. Among women who did not have hypertension at study enrollment, higher circulating proportions of B cells and lower proportions of naïve CD4+ helper T cells were associated with higher rates of subsequent hypertension incidence over 15 years of follow-up. These alterations became more pronounced after a hypertension diagnosis. Compared to participants with normal blood pressure, women with hypertension had higher circulating proportions of neutrophils and lower proportions of CD4+ helper T cells, natural killer cells, and B cells.
Together, these findings extend beyond animal models to describe how leukocyte distributions become altered during the development of human hypertension.
Citation: Kresovich JK, Xu Z, O'Brien KM, Parks CG, Weinberg CR, Sandler DP, Taylor JA. 2022. Peripheral immune cell composition is altered in women before and after a hypertension diagnosis. Hypertension; doi:10.1161/HYPERTENSIONAHA.122.20001 [Online 19 October 2022].
Reshaping our understanding of female reproductive tract development
The remnant of the male reproductive tract tissue contributes to the formation of the female reproductive tract, potentially advancing our understanding of disorders of sexual development, according to NIEHS researchers and their collaborators.
A female embryo initially possesses both the primitive female and male reproductive tracts, also known as the Müllerian and Wolffian ducts, respectively. During sexual differentiation, which is the process by which the sexual dimorphic reproductive organs are established from primitive embryonic structures, the female eliminates the Wolffian duct and maintains the Müllerian duct that eventually gives rise to the female reproductive tract organs.
Surprisingly, the researchers showed that the female embryo retains a Wolffian duct component known as the mesenchyme, even after sexual differentiation. When incorporated into the female reproductive tract organs, the Wolffian duct mesenchyme showed unique anatomical localization and gene expression patterns. Moreover, removal of this tissue stunted the growth of the fetal female reproductive tract.
Additional results showed how the hormonal environment alters the fate of the Wolffian duct mesenchyme. According to the authors, these findings reveal an unexpected contribution of male mesenchymal tissues to female reproductive tract formation and provide new perspectives on the sexual differentiation of reproductive tracts.
Citation: Zhao F, Grimm SA, Jia S, Yao HH. 2022. Contribution of the Wolffian duct mesenchyme to the formation of the female reproductive tract. PNAS Nexus 1(4):pgac182.
Hair straighteners and relaxers linked to uterine cancer
The use of hair straightening and relaxing products is positively associated with uterine cancer incidence, according to NIEHS researchers and their collaborators.
Hair products may contain hazardous chemicals with endocrine-disrupting and carcinogenic properties. Previous studies have found that hair product use is associated with a higher risk of hormone-sensitive cancers, including breast and ovarian cancer, but the relationship with uterine cancer is unclear.
To address this knowledge gap, the researchers examined the association between various hair products and uterine cancer incidence among 33, 947 women aged 35-74 years. The use of straightening and relaxing products in 12 months prior to enrollment was associated with higher rates of uterine cancer. The association was stronger for frequent use (i.e., more than four times in the past 12 months). Notably, the burden of this exposure falls predominately on Black women because of the higher prevalence of straightener and relaxer use. The use of other hair products, including dyes and permanents or body waves, was not associated with uterine cancer.
According to the authors, this study provides the first epidemiologic evidence of a relationship between the use of straightening and relaxing products and uterine cancer. Given the widespread use of hair products and the rising incidence of uterine cancer, more research is needed to confirm this novel finding and to identify specific chemicals driving this observed association.
Citation: Chang CJ, O'Brien KM, Keil AP, Gaston SA, Jackson CL, Sandler DP, White AJ. 2022. Use of straighteners and other hair products and incident uterine cancer. J Natl Cancer Inst; doi:10.1093/jnci/djac165 [Online 17 October 2022].
How a protein called Apn2/APE2 heals DNA damage
New insights reveal how a molecule called Apn2 can deal with chemically diverse forms of DNA damage, according to NIEHS researchers.
In general, nuclear genome replication is executed with high fidelity. The correctly paired nucleotide is incorporated into the growing DNA chain to avoid mutations and other forms of genome instability. But recent evidence suggests that ribonucleotides that are stably incorporated into DNA are a common source of DNA damage.
Enzymatic processing of unrepaired single ribonucleotides in genomic DNA causes a significant threat to DNA integrity. A protein called topoisomerase 1 (Top1) cuts DNA containing ribonucleotides to generate complex DNA lesions, which are resolved by APE2 (Apn2 in yeast). Until now, it has been unclear how Apn2 recognizes and repairs this DNA damage.
To answer this question, the researchers used x-ray crystal structures, biochemical analysis, and functional studies of Apn2-DNA complexes. The results revealed a wedge-and-cut mechanism underpinning Apn2 activity that mitigated Top1-induced DNA damage. The enzyme wedges and frays DNA ends, and the inactivation of Apn2 function causes mutations in budding yeast.
Taken together, the findings are consistent with an important role for Apn2 in preventing ribonucleotide-triggered genomic instability and mutations. According to the authors, more work is needed to decipher precisely how Apn2 handles DNA nicks and gaps.
Citation: Williams JS, Wojtaszek JL, Appel DC, Krahn J, Wallace BD, Walsh E, Kunkel TA, Williams RS. 2022. Molecular basis for processing of topoisomerase 1-triggered DNA damage by Apn2/APE2. Cell Rep 41(1):111448.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)