Bisphenol A and Child Vascular Health: A Preview of Future Heart Disease Risk?

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Exposures to phthalates and bisphenols have well-documented adverse effects on reproductive health and human development.¹ These endocrine-disrupting chemicals (EDCs) are also associated with obesity, hypertension, and blood vessel lesions in cross-sectional studies of adolescents and adults.^2–5 It is conceivable that processes leading to such damage start early in life and may be affected by prenatal chemical exposure.^6,7 A study recently published in Environmental Health Perspectives examined this question in children followed from gestation into childhood.⁸The authors measured phthalates and bisphenols in urine samples from 935 pregnant Generation R participants during their first, second, and third trimesters. The Generation R Study, based in Rotterdam, the Netherlands, comprises a population-based prospective cohort.⁹ At approximately 10 years of age, the women’s children underwent ultrasounds for two measurements of the common carotid artery: distensibility (elasticity) and intima-media thickness (the thickness between the intima and media layers of the vessel wall). Both distensibility and intima-media thickness reflect vascular health in the whole body^10–12; thicker vessel walls and reduced elasticity are considered distinct but overlapping risk factors for cardiovascular disease in adulthood, such as atherosclerosis.¹³Open in a separate windowThe intima layer of the artery (shown in black) is composed of endothelial cells, and the media layer (shown in pink) is made of smooth muscle and elastic fibers. Combined expansion (diastole) and contraction (systole) of the media layer pushes blood through the artery and controls blood pressure. In this transmission electron micrograph, the intima has accordioned due to contraction of the media. Image: © Steve Gschmeissner/Science Source.The authors analyzed the children’s vascular measurements in association with their mothers’ prenatal levels of three bisphenols [bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF)], low-molecular-weight phthalates as a group, high-molecular-weight phthalates, and three individual phthalates. They found no associations between any of the chemicals and distensibility. However, higher maternal urine concentrations of total bisphenols and of BPA alone were associated with thinner vessel walls in the children’s carotid artery. No associations were found for BPS, BPF, or any phthalate.The association of higher total bisphenol and BPA exposure with thinner—rather than thicker—vessel walls surprised the team initially but is biologically plausible, says first author Sophia Blaauwendraad. “Associations between higher BPA levels and atherosclerosis in adulthood [demonstrated in earlier studies¹⁴] could be due to oxidative stress that accelerates the formation of atherosclerotic plaques and thickens the vascular wall,” says Blaauwendraad, a physician and graduate student in epidemiology under senior coauthor Vincent Jaddoe at Rotterdam’s Erasmus University Medical Center. Fetal exposures, on the other hand, may be associated with an underdevelopment of the vasculature in childhood, the authors speculate. However, Blaauwendraad says, as yet no prospective studies have tracked intima-media thickness measures from childhood to adulthood.¹⁵Nikki Posnack, an assistant professor of pharmacology, physiology, and pediatrics at Children’s National Hospital in Washington, DC, says the study’s strengths include its large sample size and measurements of several subtypes of phthalates and bisphenols at three different time points during pregnancy. Posnack, who was not involved in the research, says, “This is a compelling study that opens up new opportunities for mechanistic follow-up studies in model systems.” Such studies could examine whether BPA disrupts development of blood vessels and alters their contractile properties,¹⁶ similar to the chemical’s disruption of hormonal regulation.According to Lars Lind, a professor of medicine at Uppsala University in Sweden, who also was not involved in the project, studying the effect of the chemicals on early vascular changes in animal models would be worthwhile and should be accompanied by replication efforts in other human birth cohorts. “Since the findings were unexpected, replication is critical to increase our faith in them,” says Lind. “But it is possible that these chemicals may have different effects at the fetal stage than later in life.”The association with total bisphenols appears to have been driven mainly by BPA; BPS and BPF were below the limit of detection in more than half the samples, possibly because they were collected in 2002–2006, when these chemicals were used less than today. However, human exposure to these BPA replacement chemicals has been increasing.¹⁷ “With that in mind,” Posnack says, “I think the study fills an important knowledge gap by exploring if exposure to any bisphenols in utero may affect subclinical indicators of vascular disease risk later in life.”     

Evaluation of a Wastewater-Based Epidemiological Approach to Estimate the Prevalence of SARS-CoV-2 Infections and the Detection of Viral Variants in Disparate Oregon Communities at City and Neighborhood Scales

Background: Positive correlations have been reported between wastewater SARS-CoV-2 concentrations and a community’s burden of infection, disease or both. However, previous studies mostly compared wastewater to clinical case counts or nonrepresentative convenience samples, limiting their quantitative potential.Objectives: This study examined whether wastewater SARS-CoV-2 concentrations could provide better estimations for SARS-CoV-2 community prevalence than reported cases of COVID-19. In addition, this study tested whether wastewater-based epidemiology methods could identify neighborhood-level COVID-19 hotspots and SARS-CoV-2 variants.Methods: Community SARS-CoV-2 prevalence was estimated from eight randomized door-to-door nasal swab sampling events in six Oregon communities of disparate size, location, and demography over a 10-month period. Simultaneously, wastewater SARS-CoV-2 concentrations were quantified at each community’s wastewater treatment plant and from 22 Newport, Oregon, neighborhoods. SARS-CoV-2 RNA was sequenced from all positive wastewater and nasal swab samples. Clinically reported case counts were obtained from the Oregon Health Authority.Results: Estimated community SARS-CoV-2 prevalence ranged from 8 to 1,687/10,000 persons. Community wastewater SARS-CoV-2 concentrations ranged from 2.9 to 5.1log10 gene copies per liter. Wastewater SARS-CoV-2 concentrations were more highly correlated (Pearson’s r=0.96; R2=0.91) with community prevalence than were clinically reported cases of COVID-19 (Pearson’s r=0.85; R2=0.73). Monte Carlo simulations indicated that wastewater SARS-CoV-2 concentrations were significantly better than clinically reported cases at estimating prevalence (p<0.05). In addition, wastewater analyses determined neighborhood-level COVID-19 hot spots and identified SARS-CoV-2 variants (B.1 and B.1.399) at the neighborhood and city scales.Discussion: The greater reliability of wastewater SARS-CoV-2 concentrations over clinically reported case counts was likely due to systematic biases that affect reported case counts, including variations in access to testing and underreporting of asymptomatic cases. With these advantages, combined with scalability and low costs, wastewater-based epidemiology can be a key component in public health surveillance of COVID-19 and other communicable infections. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP10289","term_id":"372009674","term_text":"EHP10289"}}EHP10289     

Reversal of glucose-induced inhibition of newborn rat liver mitochondrial maturation by administration of alkylxanthines at birth

A glucose injection given immediately after birth delays the maturation which normally occurs in rat liver mitochondria and which increases the rate of ATP synthesis coupled to succinate oxidation from a low value at birth to the adult value a few hours after birth [R. Meister, J. Comte, L. Baggetto, C. Godinot and D. C. Gautheron, Biochim. biophys. Acta 722, 36 (1983)]. Alkylxanthine (pentoxifylline, HWA 285) administration at birth has no effect on the maturation of mitochondria prepared from 2-hr-old rat livers while DBcAMP administration increases their RCR and their rate of ATP synthesis. On the contrary, both alkylxanthines and DBcAMP reverse the glucose-induced inhibition of mitochondrial maturation. This DBcAMP effect cannot be mimicked by butyrate and is therefore related to cAMP. The cAMP content of rat liver increases during this postnatal period in both control and glucose-treated rats, although glucose administration tends to decrease the level of cAMP. Alkylxanthine administration restores after 2 hr the cAMP level in glucose-treated animals. The variations of RCR could not be completely correlated with the level of cAMP. The possible involvement of other factors in the mitochondrial maturation and the glucose effect is discussed.     

Evaluation of sE-Selectin and sICAM-1 as Parameters for Renal Function

Introduction. In order to monitor acute renal failure, intensive care patients were examined, and routine as well as specialized parameters were compared. Materials and Methods. Thirty-three patients at the Surgical Intensive Care Unit (ICU) were examined daily over the entire period for which they stayed in the ICU. The patients were retrospectively classified as being either with or without acute renal failure. Group 1 consisted of 22 patients who resided in the ICU for 11–15 (median 14) days without ARF. Group 2 consisted of 11 patients who developed an ARF during their stay of 13–18 (median 16) days in the ICU. In addition to the routine parameters of diuresis, serum creatinine/urea, and clearance of creatinine, specialized parameters for kidney function, including the excretion rates of α1-microglobulin, N-acetyl-β-D-glucosaminidase, and total protein, were compared with the excretion rate of soluble ICAM-1 and sE-Selectin. Results. Diuresis, serum creatinine, urea, and enzyme elimination were pathological among patients with ARF. Already on the day of admission, raised elimination rates of sICAM-1 were found in the urine of patients who had developed an ARF. While high values were still shown upon discharge, levels kept falling among patients without ARF. Clearly raised values were also shown for sE-Selectin compared to patients without ARF. Conclusions. sICAM-1 and sE-Selectin as supplementary parameters indicating renal function revealed early signs of kidney damage. These parameters may play a major role in the development of novel therapeutic approaches for ARF (antibodies against ICAM-1 or sE-Selectin).     

Glutathione Turnover in the Kidney; Considerations Relating to the γ-Glutamyl Cycle and the Transport of Amino Acids

The overall turnover of glutathione in kidney and liver was determined in studies in which L-[¹⁴C]glutamate was administered to mice. Turnover was much more rapid (about 5 times greater) in kidney than in liver. Studies were also carried out in which 5-oxo-L-[¹⁴C]proline was administered; the first order rate constants for glutathione synthesis from 5-oxoproline in liver and kidney were not far from those found for synthesis of glutathione from glutamate in these tissues. The findings are in accord with the fact that the activities of the enzymes of the γ-glutamyl cycle are much higher in kidney than in liver. The findings of high turnover of glutathione in kidney and the rapid utilization of 5-oxoproline by this organ for glutathione synthesis are consistent with the function of the γ-glutamyl cycle in vivo and the proposed role of γ-glutamyl derivatives in amino-acid transport.