Impact of metals on pancreatic beta cell function

NIEHS grantees showed that arsenic, manganese, and cadmium can impair the function of beta cells, which synthesize and secrete insulin, but they may do so by different mechanisms.

The study examined how exposure to metals, alone and in mixtures, affects insulin regulation in pancreatic beta cells. Pancreatic beta cells recognize glucose in the body and secrete insulin as required. Because changes to glucose-stimulated insulin secretion (GSIS) are linked to type 2 diabetes risk, researchers sought to examine the effects of heavy metals on GSIS.

In beta cells, the researchers compared the effects of low-dose heavy metal exposure on GSIS and mitochondrial metabolism, a key step in the regulation of GSIS. A 24-hour exposure to arsenic, cadmium, or manganese alone significantly inhibited GSIS, with no effects from exposure to zinc. Interestingly, the researchers did not observe additive or synergistic effects on GSIS or mitochondrial function in mixtures of arsenic with either manganese or cadmium.

Although both arsenic and manganese impaired mitochondrial function, the team did not find the same effect in cells exposed to cadmium. According to the authors, these data suggest that manganese, like arsenic, may inhibit GSIS by impairing mitochondrial function, whereas cadmium may target other mechanisms that regulate GSIS in beta cells.

Citation: Dover EN, Patel NY, Styblo M. 2018. Impact of in vitro heavy metal exposure on pancreatic beta cell function. Toxicol Lett 299:137−144.

Prenatal exposure to chemicals in personal care products linked to earlier puberty in girls

Girls exposed to chemicals commonly found in personal care products before birth may hit puberty earlier, according to an NIEHS-funded study. The study found that mothers who had higher levels of diethyl phthalate and triclosan in their bodies during pregnancy had daughters who experienced puberty at younger ages. Diethyl phthalate is often used as a stabilizer in fragrances and cosmetics. The antimicrobial agent triclosan was widely used in hand soap until it in 2017, although it is still used in some toothpastes.

The results came from data collected as part of the Center for the Health Assessment of Mothers and Children of Salinas study, which followed 338 children from before birth to adolescence. The researchers measured a variety of chemicals found in personal care products, including phthalates, parabens, and phenols, in urine samples from mothers, taken twice during pregnancy, and from children at age 9 years. They assessed pubertal timing every 9 months between ages 9 and 13 years using Tanner Staging, an objective classification system used to document the development of secondary sex characteristics of children during puberty.

In girls, they found that higher prenatal urinary concentrations of triclosan and one of its degradation products were associated with an earlier first occurrence of menstruation, and that higher prenatal concentrations of the main metabolite of diethyl phthalate were associated with earlier onset of pubic hair development. The same trends were not observed in boys. They also observed a link between urinary metabolites of parabens at age 9 years with earlier puberty. However, this may reflect reverse causality, because children going through puberty earlier may be more likely to use personal care products.

Citation: Harley KG, Berger KP, Kogut K, Parra K, Lustig RH, Greenspan LC, Calafat AM, Ye X, Eskenazi B. 2018. Association of phthalates, parabens and phenols found in personal care products with pubertal timing in girls and boys. Hum Reprod 34(1):109–117. (Story)

New gene sheds light on effects of chemical exposures

NIEHS grantees found a new gene in zebrafish that could lead to a better understanding of how exposure to chemicals leads to disease in humans. The study describes the interactions between chemicals that can activate the aryl hydrocarbon receptor (AHR), which is a protein involved in regulating a number of biological responses, and the newly discovered gene, known as slincR.

A variety of chemicals, including dioxins and polycyclic aromatic hydrocarbons (PAHs), can activate AHR, contributing to adverse health effects in humans and wildlife. In zebrafish, an important gene in human development, sox9b, is repressed in several AHR-mediated toxic responses, including developmental malformations.

In the study, researchers demonstrated that slincR represses sox9b in response to dioxin exposure. They also found that slincR expression may play a causal role in dioxin-induced developmental effects and can regulate cartilage development. In addition, slincR expression was significantly increased by exposure to a number of environmentally relevant PAHs.

The study team identified genes in humans and mice that perform the same function as slincR, supporting the human health relevance of the model. According to the authors, these data improve what we know about AHR activation by environmental pollutants and may be used to predict the types of compounds that will react with the AHR receptor.

Citation: Garcia GR, Shankar P, Dunham CL, Garcia A, La Du JK, Truong L, Tilton SC, Tanguay RL. 2018. Signaling events downstream of AHR activation that contribute to toxic responses: the functional role of an AHR-dependent long noncoding RNA (slincR) using the zebrafish model. Environ Health Perspect 126(11):117002.

Early-life metal exposures linked to children’s behavior problems

NIEHS grantees reported that early-life metal exposures, as measured in baby teeth, were associated with behavioral problems in children, and the associations were dependent upon developmental timing of exposure. According to the authors, these findings suggest that the developing brain is uniquely vulnerable to metal exposures at different timepoints.

The researchers estimated prenatal and postnatal manganese, zinc, and lead levels in naturally shed baby teeth from 133 subjects enrolled in a longitudinal birth cohort study in Mexico City. Using an innovative laser ablation method, they reconstructed exposures to manganese, zinc, and lead from teeth histories, to a scale of 1-2 weeks, and identified markers of exposure at discrete developmental periods. They also measured behavior at 8-11 years of age.

They found that early postnatal exposure to manganese, lead, or zinc was associated with increased anxiety symptoms. When examined as a metal mixture, the researchers observed two potential windows of susceptibility to increased anxiety symptoms. Exposures during 0-8 months of age appeared to be driven by manganese. The second window, exposures at 8-12 months of age, was driven by metal mixture and dominated by lead.

Higher prenatal manganese in teeth was linked to a decrease in childhood behavioral problems, specifically hyperactivity and attention. In contrast, postnatal dentine manganese was associated with higher anxiety. According to the authors, these results suggest that prenatal dentine manganese may be protective, whereas excessive early postnatal manganese may increase risk of adverse behaviors, which emphasized the importance of exposure timing.

Citation: Horton MK, Hsu L, Claus Henn B, Margolis A, Austin C, Svensson K, Schnaas L, Gennings C, Hu H, Wright R, Rojo MMT, Arora M. 2018. Dentine biomarkers of prenatal and early childhood exposure to manganese, zinc and lead and childhood behavior. Environ Int 121(Pt 1):148—158.