Environmental Factor – August 2022: Intramural Papers of the Month

DNTP study shows how PFAS might harm the placenta

Per- and polyfluoroalkyl substances (PFAS) may directly target the placenta, disrupting cellular function and the activity of genes that are critical for proper development, well below toxic levels, according to researchers from the NIEHS Division of the National Toxicology Program (DNTP).

PFAS are ubiquitous environmental contaminants that have been associated with pregnancy complications involving the placenta, which delivers oxygen and nutrients to the fetus. Adverse developmental and reproductive outcomes have been investigated for relatively few PFAS, and the underlying mechanisms remain unclear. There is an immense knowledge gap regarding the placental toxicity of the more than 600 PFAS compounds currently in United States commerce.

Using a high-throughput toxicity screen (HTTS), the researchers evaluated the effects of 42 PFAS on human placental cells called trophoblasts. According to the authors, this work describes the first PFAS HTTS using a placental cell line. Several compounds of high public health interest severely inhibited trophoblast migration, which is important for embryonic implantation, fetal growth, and the prevention of certain pregnancy complications.

Two of these compounds — perfluorooctanoic acid (PFOA) and ammonium perfluoro-2-methyl-3-oxahexanoate (GenX) — altered the activity of genes that are vital to placental health and cellular responses to stress at treatment levels 5- to 150-fold lower than those causing cytotoxicity. Taken together, the results highlight the potential of these compounds to disrupt critical aspects of trophoblast biology, such as proliferation, migration, and mitochondrial function.

Citation: Blake BE, Rickard BP, Fenton SE. 2022. A high-throughput toxicity screen of 42 per- and polyfluoroalkyl substances (PFAS) and functional assessment of migration and gene expression in human placental trophoblast cells. Front Toxicol 4:881347.

Researchers explore how environment may affect cardiovascular health

A first-of-its-kind study has revealed novel associations between a wide range of environmental factors and various cardiovascular outcomes, with important public health implications, according to NIEHS researchers.

Cardiovascular disease accounts for nearly one-quarter of all deaths and is the leading cause of mortality in the United States. Yet many environmental exposures that may contribute to cardiovascular problems have not been examined.

To address this knowledge gap, the researchers conducted an exposome-wide association study (ExWAS) — a powerful new approach that simultaneously considers multiple exposures without bias and systematically prioritizes risk factors linked to disease outcomes. According to the authors, this study is the first ExWAS performed across multiple cardiovascular-related outcomes in an adult population in the United States.

The researchers collected survey data on 502 environmental exposures and the health histories of 5,015 participants enrolled in the North Carolina Personalized Environment and Genes Study (PEGS). ExWAS analyses revealed novel associations between blood type A (Rh-) and heart attack, as well as paint exposures and stroke. Additional risk factors include sleep disorder, smoking, and a family history of blood clotting problems, while regular intake of grapefruit was associated with reduced risk. By contrast, higher paternal education level is linked to a lower risk of multiple disease outcomes. Taken together, the results could be used to efficiently target modifiable risk factors for patients with cardiovascular conditions.

Citation: Lee EY, Akhtari F, House JS, Simpson RJ Jr, Schmitt CP, Fargo DC, Schurman SH, Hall JE, Motsinger-Reif AA. 2022. Questionnaire-based exposome-wide association studies (ExWAS) reveal expected and novel risk factors associated with cardiovascular outcomes in the Personalized Environment and Genes Study. Environ Res 212(Pt D):113463.

Injectable contraceptive use may help combat uterine tumors

The development of nonmalignant tumors called uterine leiomyomas could be curtailed by a long-acting, progestin-only injectable contraceptive called depot medroxyprogesterone acetate (DMPA [Depo-Provera]), according to NIEHS researchers and their collaborators.

Uterine leiomyomas develop in up to 80% of women and can cause debilitating symptoms such as heavy menstrual bleeding, anemia, and pelvic pain. Women’s fibroids often grow in size and number, requiring invasive treatments that can have medical risks and limit desired pregnancies. Identifying factors that reduce incidence or slow growth is vital to limiting the burden of this health condition, which disproportionately affects Black women.

In a well-designed prospective study of 1,693 Black women between the ages of 23 and 35 years and who had no previous leiomyoma diagnosis, the researchers found that DMPA reduced leiomyoma burden. Compared with those who never used the contraceptive, participants exposed to DMPA within the previous two years experienced a 40% reduction in leiomyoma incidence, 42% lower tumor growth, which had essentially stopped, a twofold greater chance of leiomyoma shrinkage, and 60% greater tumor loss.

According to the authors, such changes in early leiomyoma development in young women could delay symptom onset and limit the need for invasive treatment.

Citation: Harmon QE, Patchel SA, Zhao S, Umbach DM, Cooper TE, Baird DD. 2022. Depot medroxyprogesterone acetate use and the development and progression of uterine leiomyoma. Obstet Gynecol 139(5):797–807.

Vitamin D may protect against breast cancer in Black, Hispanic women

A prospective study suggests that vitamin D might reduce the incidence of breast cancer in non-Black Hispanic/Latina and Black/African American women, according to NIEHS researchers and their collaborators.

Observational studies have provided evidence that vitamin D may protect against some chronic diseases, including breast cancer. Although Black and Hispanic women tend to have lower circulating vitamin D levels than non-Hispanic White women, few studies have examined the association between vitamin D and breast cancer within these groups.

To address this knowledge gap, the researchers analyzed total 25-hydroxyvitamin D — a biomarker of vitamin D exposure — in blood samples collected from 1,960 Black/African American and non-Black Hispanic/Latina women. All participants had at least one sister with breast cancer but had never previously received this diagnosis themselves.

Women with circulating 25-hydroxyvitamin D concentrations above the clinical cut point for deficiency (20 ng/mL) at the time of enrollment had lower breast cancer rates during an average follow-up of nine years, compared with participants who had concentrations lower than this threshold. This result was stronger for Hispanic/Latina women than for Black/African American participants.

According to the authors, these findings highlight a possible path for breast cancer intervention in two racial/ethnic groups with a high prevalence of vitamin D deficiency.

Citation: O’Brien KM, Harmon QE, Jackson CL, Diaz-Santana MV, Taylor JA, Weinberg CR, Sandler DP. 2022. Vitamin D concentrations and breast cancer incidence among Black/African American and non-Black Hispanic/Latina women. Cancer 128(13):2463–2473.

High-resolution structures show how enzymes may regulate DNA building blocks

Structural and biochemical data offer new insights into the catalytic mechanism of a critical class of enzymes called deoxynucleoside triphosphate (dNTP) triphosphohydrolases (dNTPases), according to NIEHS researchers and their collaborators.

These enzymes perform key cellular functions such as regulating pools of dNTPs — the building blocks of DNA — and contribute to immunity against viruses. Abnormal dNTP levels can lead to defective DNA replication or strongly elevated mutation rates. Low activity of a human dNTPase called sterile alpha motif and HD domain–containing protein 1 (SAMHD1) leads to an autoimmune disease known as Aicardi–Goutières syndrome, further highlighting the importance of these enzymes for human health.

To obtain deeper insight into structural and mechanistic features of this class of enzymes, the researchers investigated a SAMHD1 homolog from the marine bacterium Leeuwenhoekiella blandensis. They presented X-ray crystallographic structures of enzyme variants in catalytically important conformations and obtained the highest resolution cryo-electron microscopy structures of any SAMHD1-like dNTPase to date.

The results revealed a novel regulatory feature that may facilitate the maintenance of cellular dNTP pools in L. blandensis. According to the authors, this bacterium could be an attractive model organism for future studies on mechanisms that balance dNTP pools and circuits that control nucleotide metabolism.

Citation: Klemm BP, Sikkema AP, Hsu AL, Horng JC, Hall TMT, Borgnia MJ, Schaaper RM. 2022. High-resolution structures of the SAMHD1 dGTPase homolog from Leeuwenhoekiella blandensis reveal a novel mechanism of allosteric activation by dATP. J Biol Chem 298(7):102073.