Enzyme acts as sensor for high manganese levels in cells

An enzyme called prolyl hydroxylase domain 2 (PHD2) may detect and regulate changes in manganese levels in cells, according to a study funded by NIEHS.

Manganese is an essential mineral, but high levels in the brain are linked to Parkinson-like diseases in humans. The researchers previously found that elevated manganese in cells coincided with increases in hypoxia-induced factors (HIFs), which are proteins that activate genes that allow cells to adapt to environmental stressors. For example, HIF activates a transporter that removes excess manganese from cells.

Normally, PHD2 binds with iron to degrade HIF, and the absence of HIF prevents the manganese transporter from working optimally. Because HIF is necessary for triggering excess manganese removal, the scientists hypothesized manganese must interfere with PHD2 and therefore protect the function of HIF.

To test this, the team measured normal PHD2 activity in the absence of manganese. Then, they looked at changes in PHD2 when it was exposed to manganese, exposed to manganese and then to iron, or exposed to manganese and iron simultaneously.

The presence of manganese blocked PHD2 activity but adding iron increased it. When PHD2 was exposed to iron and manganese simultaneously, the enzyme’s activity decreased when there was a higher ratio of manganese and was restored when there was a higher ratio of iron. Moreover, activity of a mutated version of PHD2 that could bind iron, but not manganese, was not blocked by manganese. According to the researchers, this suggests that iron and manganese compete to bind with PHD2. High manganese levels block PHD2, preventing it from degrading HIF, which allows HIF to activate the manganese transporter gene and to help regulate manganese levels.

These findings identify PHD2 as a manganese sensor within cells and show how its deactivation triggers manganese regulation through HIF, according to the authors. They also noted this knowledge may help scientists develop new therapeutics for manganese-induced neurological diseases. (MZ)

Citation: Gurol KC, Jursa T, Cho EJ, Fast W, Dalby KN, Smith DR, Mukhopadhyay S. 2024. PHD2 enzyme is an intracellular manganese sensor that initiates the homeostatic response against elevated manganese. Proc Natl Acad Sci 121(26):e2402538121.

Scientists detect potentially harmful metals in tampons

Tampons may contain traces of certain metals, according to a study funded in part by NIEHS. Tampons are commonly used to manage menstrual bleeding. Because the vaginal membrane easily absorbs certain substances, such as chemicals that may have adverse health effects, knowing what is inside tampons is important.

To identify metals present in tampons, the scientists analyzed 30 tampons from different brands. They used acid to break down the tampon material and mass spectrometry — a laboratory technique that can measure even trace metals in environmental or biological samples — to test the tampons for 16 different metals. The team then compared the concentrations of metals by tampon brand, applicator material, region of purchase, and organic versus nonorganic tampons.

The researchers detected all 16 metals across the samples and 12 metals in every tampon sample, although concentrations varied widely between brands. The highest concentrations were of essential, nontoxic metals like zinc and calcium, which are needed by the body in small amounts. In contrast, arsenic had the lowest concentration among the metals detected but was detected in 95% of samples. All samples contained levels of toxic metals, including cadmium, vanadium, and lead. Lead is a toxic metal with no safe exposure level.

According to the researchers, this study is one of the first to measure concentrations of metals in tampons. They noted it is unclear if metals can transfer from tampons into the body to potentially cause harm. (MZ)

Citation: Shearston JA, Upson K, Gordon M, Do V, Balac O, Nguyen K, Yan B, Kioumourtzoglou MA, Schilling K. 2024. Tampons as a source of exposure to metal(loid)s. Environ Int 190:108849.

Mobile monitoring detects high levels of cancer-causing chemical in Louisiana air

Using mobile monitors, NIEHS-funded researchers reported high levels of ethylene oxide (EtO) in southeastern Louisiana air. EtO, a volatile organic compound used to produce other chemicals, is associated with blood and breast cancers. Facilities in this area — where high cancer rates have been linked to industrial air pollution — emit some of the highest levels of EtO in the U.S.

The researchers installed air pollutant monitors on two vehicles, or mobile laboratories, including two EtO instruments. In February 2023, both vehicles drove sampling routes in southeastern Louisiana where the EtO-emitting facilities are most dense. One vehicle focused on identifying emission sources of EtO and quantifying the amount of hazardous pollutants the public was inhaling. The other drove routes to better sample EtO plumes. They summarized their data in 500-meter blocks and compared their results to U.S. Environmental Protection Agency (EPA) EtO estimates.

All measurements from the mobile laboratories were higher than EPA estimates. The average EtO concentration measured was 31.4 parts per trillion (ppt). In 75% of the blocks tested, EtO levels were above 10.9 ppt, which is the upper limit of EPA’s lifetime acceptable cancer risk. EtO levels near facilities emitting EtO, representing about 3% of locations, were more than ten times that level, representing a serious potential health hazard for facility workers. The researchers also identified 192 EtO plumes, some as far as seven miles away from likely emissions sources and within reach of nearby schools and residential areas.

According to the authors, study findings demonstrate that a mobile monitoring system can provide more precise and accurate measurements of exposure to cancer-causing air pollutants in a key industrial region. (AL)

Citation: Robinson ES, Tehrani MW, Yassine A, Agarwal S, Nault BA, Gigot C, Chiger AA, Lupolt SN, Daube C, Avery AM, Claflin MS, Stark H, Lunny EM, Roscioli JR, Herndon SC, Skog K, Bent J, Koehler K, Rule AM, Burke T, Yacovitch TI, Nachman K, DeCarlo PF. 2024. Ethylene oxide in southeastern Louisiana's petrochemical corridor: high spatial resolution mobile monitoring during HAP-MAP. Environ Sci Technol. 58(25):11084-95.

Yeast-based method capable of rapidly screening chemicals for reproductive toxicity

NIEHS-funded researchers demonstrated that tests using yeast can rapidly screen large numbers of chemicals to identify those that may harm reproductive health. The method can help prioritize chemicals for future studies and inform regulatory decisions.

Many chemicals have not been evaluated for reproductive toxicity because traditional methods using humans or rodents are difficult, costly, and time-consuming. Yeast cells share many genes and proteins with humans, offering a useful alternative for testing. The researchers looked at how chemicals disrupt meiosis, a type of cell division that produces sex cells and is crucial for reproduction.

The researchers exposed yeast cells to 199 chemicals, including bisphenols, phthalates, and PFAS. Some of the chemicals tested were known to harm the reproductive system, and some lack data on reproductive toxicity. Then, they measured how far cells progressed through meiosis. They also examined non-reproductive cell division to determine whether chemicals had other effects on cell growth.

The team classified 57 chemicals as reproductive toxicants in yeast. Of these, 17 affected only meiosis and 40 affected both meiosis and cell growth. They also compared results for bisphenol A (BPA), a compound known to harm the reproductive system and largely phased out of general use, with newer BPA substitutes, reporting many substitutes to be more toxic than the original compound. When BPA and its substitutes were combined, reproductive outcomes worsened.

For chemicals known to harm the reproductive system in mammals, the toxicity seen in yeast was similar. However, many of the chemicals identified as potential reproductive toxins in yeast have not yet been tested in mammals. According to the authors, this method is a promising approach to rapidly assess and prioritize chemicals for further study. (AL)

Citation: Kumar R, Oke A, Rockmill B, de Cruz M, Verduzco R, Shodhan A, Woodruff-Madeira X, Abrahamsson DP, Varshavsky J, Lam J, Robinson JF, Allard P, Woodruff TJ, Fung JC. Rapid identification of reproductive toxicants among environmental chemicals using an in vivo evaluation of gametogenesis in budding yeast Saccharomyces cerevisiae. Reprod Toxicol 128:108630.