Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?

According to the "Developmental Origins of Health and Disease" (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.

Arterial structure and function and environmental exposure to cadmium.

OBJECTIVES: Few studies have addressed the effect of cadmium toxicity on arterial properties. METHODS: We investigated the possible association of 24 h urinary cadmium excretion (an index of lifetime exposure) with measures of arterial function in a randomly selected population sample (n = 557) from two rural areas with low and high environmental exposure to cadmium. RESULTS: 24 h urinary cadmium excretion was significantly higher in the high compared with the low exposure group (p<0.001). Even though systolic (p = 0.42), diastolic (p = 0.14) and mean arterial pressure (p = 0.68) did not differ between the high and low exposure groups, aortic pulse wave velocity (p = 0.008), brachial pulse pressure (p = 0.026) and femoral pulse pressure (p = 0.008) were significantly lower in the high exposure group. Additionally, femoral distensibility (p<0.001) and compliance (p = 0.001) were significantly higher with high exposure. Across quartiles of 24 h urinary cadmium excretion (adjusted for sex and age), brachial (p for trend = 0.015) and femoral (p for trend = 0.018) pulse pressure significantly decreased and femoral distensibility (p for trend = 0.008) and compliance (p for trend = 0.007) significantly increased with higher cadmium excretion. After full adjustment, the partial regression coefficients confirmed these associations. Pulse wave velocity (beta = -0.79+/-0.27; p = 0.004) and carotid (beta = -4.20+/-1.51; p = 0.006), brachial (beta = -5.43+/-1.41; p = 0.001) and femoral (beta = -4.72+/-1.74; p = 0.007) pulse pressures correlated negatively, whereas femoral compliance (beta = 0.11+/-0.05; p = 0.016) and distensibility (beta = 1.70+/-0.70; p = 0.014) correlated positively with cadmium excretion. CONCLUSION: Increased cadmium body burden is associated with lower aortic pulse wave velocity, lower pulse pressure throughout the arterial system, and higher femoral distensibility.

Crohn's disease with adenocarcinoma and dysplasia. Macroscopical, histological, and immunohistochemical aspects of two cases.

We present two cases of small-bowel adenocarcinoma and dysplasia in patients with longstanding Crohn's disease. In one case, the dysplasia and cancer were exclusively located in the terminal ileum, whereas in the other case, several cancers were found from the ileum toward the transverse colon. In both cases, we found a clinically unsuspected Dukes C1 mucinous adenocarcinoma together with large foci of polypoid villous dysplasia or with multifocal high-grade dysplasia and intramucosal carcinoma. Immunohistochemical staining for carcinoembryonic antigen (CEA) revealed a different staining pattern in various diseased areas. The intensity of CEA staining paralleled the histologic degrees of dysplasia and neoplasia. Cytokeratin expression was disturbed in inflamed mucosa, and it was more pronounced in high-grade dysplasia and invasive carcinoma. We conclude that the presence of dysplasia in an intestinal biopsy of a patient with Crohn's disease should arouse the pathologist's suspicion of carcinoma and force him or her to take multiple sections from strictures and polypoid lesions, especially since the clinical symptoms of a carcinoma may be obscured by the symptoms of inflammatory bowel disease. Immunohistochemical staining with CEA and cytokeratin are useful in the objectivation of dysplasia.

Extranodal non-Hodgkin's lymphoma of the head and neck.

Forty-six patients referred to our department between 1970 and 1982 with biopsy proven extranodal non-Hodgkin's lymphoma (NHL) of the head and neck were analysed. The median follow-up was 78 months. As a result of histological revision, six cases were excluded. By retrospective staging, 10 patients were found to have advanced disease (stage IV) at the moment of presentation, and three showed infradiaphragmatical nodes (stage III). All stage I-II patients except one were treated with radiotherapy. The 5-year actuarial relapse-free survival was 50% for the whole group, and 77% for the 26 patients who achieved complete remission after initial treatment. All stage IV patients died from lymphoma. Initial response and localised disease were the most significant prognostic features.

Characterization of cadmium proteinuria in man and rat.

In workers chronically exposed to cadmium and without signs of renal insufficiency, plasma proteins with molecular weight ranging from 11,800 to 450,000 are excreted in greater amount in urine. Increased urinary excretion of low and high molecular weight proteins can occur independently. Because of its greater stability in urine and provided a sensitive immunological technique is used, the determination of retinol-binding protein is a more practical and reliable test of proximal tubular function than beta 2-microglobulin. The evaluation of renal function of workers removed from cadmium exposure indicates that cadmium-induced renal lesions, albeit of slow progression, are not reversible when exposures ceases. In workers chronically exposed to cadmium or removed from cadmium exposure, metallothionein in urine is directly correlated with cadmium in urine but not with cadmium in blood or years of cadmium exposure. The association between cadmium in urine and metallothionein in urine is independent of the status of renal function and the intensity of current exposure to cadmium. Whereas the repeated IP injection of high doses of cadmium to rat gives rise to a mixed or tubular type proteinuria, the prolonged oral administration of cadmium results mainly in the development of a glomerular type proteinuria. The former is usually reversible after cessation of treatment whereas the latter is not. Circulating antiglomerular basement membrane antibodies have been found in man and in rat chronically exposed to cadmium. The pathogenic significance of this finding deserves further investigation.

Investigations on the lung and kidney function in workers exposed to cadmium.

The kidney seems more sensitive to the chronic effect of cadmium than the lung. Only minor impairments of lung function (mild form of obstructive lung disease) were found after long-term occupational exposure (less than 20 yr) to moderate concentration of cadmium oxide dust and fume. This conclusion, cannot, however be extrapolated to acute or subacute inhalational exposure. The nephrotoxicity of cadmium consists in a tubular dysfunction characterized by an increased excretion of beta 2-microglobulin and giving rise to the classical tubular proteinuria and in a glomerular dysfunction evidenced by an increased excretion of high molecular weight proteins and increased levels of beta 2-microglobulin and creatinine in plasma and giving rise to a glomerular type proteinuria. These renal changes were mainly found in workers whose cadmium concentration at time of the survey exceeded 1 microgram Cd/100 ml in blood and 10 microgram Cd/g creatinine in urine. It should, however, be stressed that higher levels of Cd in blood and in urine are not necessarily associated with the presence of excessive proteinuria. In newly exposed workers, the Cd level in blood increases progressively to a plateau after several weeks. Cadmium level in urine fluctuates more. In workers exposed for several months to an airborne concentration exceeding 200 microgram/m3, Cd concentration in urine seems mainly influenced by recent exposure.

Investigations of factors influencing exposure and response to lead, mercury, and cadmium in man and in animals.

The susceptibility of the heme biosynthetic pathway to lead, as reflected by increased free erythrocyte porphyrin (FEP) concentration, is in humans as well as in rats in the order of young greater than or equal to female greater than male. The difference between adult male and female rats can be explained at least partially by the interaction of estradiol and progesterone with the FEP response to lead; the hormonal influence on FEP does not seem to be mediated through changes in plasma iron. The classical "tubular type" proteinuria in workers chronically exposed to cadmium has two not necessarily concomitant components, namely, a tubular type and a glomerular type component characterized by increased excretion of low and high molecular weight proteins, respectivley. No synergistic effect of cadmium and lead on the proteinuria of workers simultaneously exposed to both metals was observed. Mercury (most likely methylmercury) is freely transferred from the mother to the fetus; there is only a slight placental barrier for lead and a rather strong one for cadmium. Compared to maternal blood, placenta does not accumulate lead or mercury but concentrates cadmium about 10-fold.

The relationship between blood pressure and environmental exposure to lead and cadmium in Belgium.

The question whether in the general population environmental exposure to lead and cadmium influences blood pressure after controlling for confounding factors remains debated. The environmental exposure of the Belgian population to both lead and cadmium is high as compared with other countries. The Cadmibel Cooperative Study was therefore designed to elucidate whether environmental exposure to lead and cadmium has any effect on blood pressure and renal function in the population at large. Before embarking on the large Cadmibel project, a small study was conducted. Blood pressure and the 24-hr urinary excretion of cadmium (CdU) and lead (PbU) were determined in a random 4% sample of the population of a small Belgian town. CdU averaged 0.27 micrograms/24 hr in 46 youths (mean age 14 +/- 3 years, +/- SD), increased with age, and was higher in 57 adult men (age 41 +/- 14 years), as compared with 59 adult women (age 39 +/- 14 years) (1.05 vs. 0.81 micrograms/24 hr; p less than 0.01). PbU averaged 5.8 micrograms/24 hr in youths and similarly increased with age; adult men excreted more lead than women (13.3 vs. 8.3 micrograms/24 hr; p less than 0.001). Among men, manual workers excreted more cadmium (1.4 vs. 0.8 micrograms/24 hr; p less than 0.05) but a similar amount of lead (7.0 vs. 6.9 micrograms/24 hr) as compared with office workers. In simple regression analysis, CdU was positively correlated with both systolic (r = 0.30; p less than 0.05) and diastolic (r = 0.38; p less than 0.01) blood pressure in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Blomstrand lethal osteochondrodysplasia.

We present the clinical, roentgenographic, and histologic abnormalities in a stillborn infant with Blomstrand osteochondrodysplasia. Parental consanguinity and multiplex occurrence in the patients' sibship confirm the hypothesis of autosomal recessive inheritance of this monogenic lethal entity. The unknown genetic defect interferes severely with skeletal growth through lack of chondrocyte multiplication and apparent uncoupling of the processes of enchondral ossification and skeletal growth.

Image cytometry determination of ploidy level, proliferative activity, and nuclear size in a series of 314 transitional bladder cell carcinomas.

Image cytometry was carried out on 281 superficial (Ta and T1) and 33 invasive (T2 to T4) bladder cancers. The parameters used to characterize these bladder tumors were: (1) histopathological grading, (2) clinical staging, (3) tumor size, (4) deoxyribonucleic acid (DNA) index (DI), (5) DNA histogram type (DHT), (6) percentage of euploid (diploid plus tetraploid) cells, (7) percentage of polyploid cells (> 5C DNA content), (8) proliferative activity (S phase fraction value), and (9) nuclear area (NA). The proliferative activity of the tumors was not related to either histopathological grade or to clinical stage, but it was related to the DHT parameter, which made it possible to identify diploid, hyperdiploid, triploid, hypertriploid, tetraploid, and polymorphic tumors. The hypertriploid tumors exhibited a significantly lower proliferative activity than the nonhypertriploid ones. Although both the DI and the NA values correlated significantly with histopathological grading, only the NA values correlated significantly with clinical staging. We further observed that some grade III bladder tumors were definitely diploid, whereas some grade I tumors were highly aneuploid. We thus hypothesize that the ploidy level of a given tumor reflects its age directly and its aggressiveness only very indirectly. In our opinion aneuploidy is only an indirect marker of aggressiveness because it reflects the fact that a malignant tumor is old, ie, has been present in a patient over a long period of time and has had ample time to express its malignancy at the clinical level. A significant relationship was accordingly obtained between tumor size and ploidy level with the highest proportion of aneuploid tumors and the highest percentage of polyploid cell nuclei being observed among the largest bladder tumors.

Adamantinoma of the tibia with pulmonary metastases and hypercalcemia.

Adamantinomas of long bones are rare primary malignant bone tumors. A case of a woman who died of pulmonary metastases of an adamantinoma of the tibia is presented. A unique feature of this case is the association with hypercalcemia. The association of hypercalcemia, hypophosphatemia, decreased parathyroid hormone levels and increased urinary cAMP excretion suggests a humorally mediated hypercalcemia. Histologic and ultrastructural analysis of the pulmonary metastases demonstrated that the tumor was composed of a heterogeneous cell population with mesenchymal and epithelial differentiation.

Cyanoacrylate tissue adhesive for closing skin wounds: a double blind randomized comparison with sutures.

A comparative double blind randomized study was undertaken in the rat, to compare the external cosmetic and the morphologic aspect of skin wounds, treated by the local application of adhesive glue (ethyl-2-cyanoacrylate-Mediglue) or classical suture technique. Skin incisions were applied and treated by a plastic surgeon, then photographed or biopsied, and evaluated and scored by independent observers, not aware of the initial treatment. Small (1.5 cm) or long (8 cm) incisions were made, on both sides of the back, and treated randomly on one side by glue and on the other side by sutures. Evaluations were performed at 1, 2, 4 and 8 wk. Both small and large wounds scored identically, irrespective of the treatment (overall score 1.5 cm wounds: 8.8 +/- 1.4 for glue versus 8.8 +/- 1.0 for sutures; 8 cm wounds: 8.3 +/- 1.9 versus 8.3 +/- 1.5; P = not significant). A morphological study demonstrated no adverse effects for the adhesive treatment, with a minor inflammatory infiltrate. Sutured wounds had a higher tendency to develop abscesses and/or major inflammation. Adhesive-treated wounds scored better than non-treated wounds (8.9 +/- 1.3 versus 7.4 +/- 3.3, P < 0.01). In conclusion, this controlled comparative study shows no difference in cosmetic aspect between adhesive and suture-treated skin incisions. Morphologically, the glue treatment is not related to any adverse effect or damage to the skin structures.

Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Public Health and Environmental Exposure to Cadmium Study Group.

This prospective population study investigated in a random sample of 692 subjects (age 20-83 years) how changing environmental exposure to cadmium influenced blood pressure (BP) and the incidence of hypertension. At baseline (1985 to 1989; participation rate, 78%) and follow-up (1991 to 1995; re-examination rate, 81%), blood pressure was measured by conventional sphygmomanometry (CBP; 15 readings in total) and, at follow-up, also by 24-h ambulatory blood pressure monitoring (ABP). Systolic/diastolic CBP at baseline averaged 128.4/77.3 mm Hg. At baseline, blood cadmium concentration (B-Cd) and urinary cadmium excretion (U-Cd) averaged (geometric means) 11.1 nmol/L and 10.2 nmol/24 h. Over 5.2 years (median follow-up), B-Cd fell by 29.6% and U-Cd by 15.2%. B-Cd fell less in subjects living closer to three zinc smelters and in premenopausal women. During follow-up, systolic CBP decreased by 2.2 mm Hg in men and remained unchanged in women, and diastolic CBP increased by 1.8 mm Hg in both sexes. No relationship could be demonstrated between the secular trends in CBP and B-Cd or U-Cd or between B-Cd or U-Cd at baseline and the incidence of hypertension. In addition, in cross-sectional analyses involving the average of all available CBP measurements in each participant or 24-h ABP at follow-up (mean, 119.1/71.4 mm Hg), blood pressure was not correlated with B-Cd or U-Cd. In conclusion, environmental exposure to cadmium was not associated with higher CBP or 24-h ABP or with increased risk for hypertension. The lesser fall in B-Cd in the residents living closer to the zinc smelters or in premenopausal women underscores the necessity to sanitize cadmium-polluted areas and to systematically reinforce the preventive measures to be adopted by exposed communities to reduce cadmium uptake.

Image cytometry analysis of Feulgen-stained nuclei in 72 lipomatous lesions including atypical lipomas and well-differentiated liposarcomas.

Well-differentiated lipomatous tumors constitute a histopathologic category whose nomenclature has been controversial, particularly with respect to the distinction between atypical lipomas of the extremities and well-differentiated liposarcomas of the retroperitoneum. To determine whether there were differences in image analytic parameters between these neoplasms, 72 lesions including 21 typical lipomas, 7 atypical lipomas, 16 retroperitoneal and 5 nonretroperitoneal well-differentiated, 9 dedifferentiated, and 14 pleomorphic liposarcomas were submitted to the computer-assisted microscopic analysis of Feulgen-stained nuclei. This methodology enabled four groups of variables to be calculated. These included: (1) quantitative chromatin pattern description (14 variables); (2) the measurement of proliferative activity (1 variable); (3) nuclear DNA content (DNA ploidy level, 5 variables); and (4) the measurement of cell density and topographical cell nuclei organization (2 variables). The results strongly suggest that atypical lipomas, whether superficial or deep, and well-differentiated liposarcomas, whether retroperitoneal or not, belong to the same category in terms of the variables analyzed.

Cytogenetic investigation of a case of congenital fibrosarcoma.

Cytogenetic studies were performed on a fibrosarcoma of a newborn. Only numerical chromosome changes (+8, +11, +20) were identified in this rare but distinct soft tissue sarcoma that occurs in children less than 5 years old.

Dumb-bell sarcoma of the foramen jugulare with syringomyelia. A radio-induced tumour?

The clinicopathological findings of a 50-year-old man, who developed cervicothoracic syringomyelia at the age of 25 are presented. He was given radiation therapy at the age of 33. At the age of 57 he developed a foramen jugulare syndrome on the left, caused by a low grade leiomyosarcoma. Etiologically, the most attractive hypothesis appears to be that the tumour was induced by radiation therapy administered 24 years previously.

Determination of manganese in blood and urine by flameless atomic absorption spectrophotometry.

A method for the determination of manganese in blood and urine is described. A chelate fo manganese with cupferron is extracted with methylisobutylketone and determined by flameless atomic absorption spectrophotometry. The method is directly applicable to urine but the determination of manganese in blood required a preliminary digestion step. With the use of internal standards, this technique allows the determination of manganese concentrations of the order of 1 mug/1 of urine or 1 mug/100 ml whole blood.

Human urinary protein 1: evidence for identity with the Clara cell protein and occurrence in respiratory tract and urogenital secretions.

Protein 1 (P1), a low mol mass urinary protein of unknown function, has been purified, sequenced and quantified in human biological fluids. The molecular size, subunit composition and partial amino acid sequence of P1 are similar to those of the 10 kDa Clara cell protein (CC10), a lung secretory protein. P1 is found in high concentrations in sputum, bronchoalveolar lavages, urine and semen of healthy individuals and in urine of some pregnant women. Contrary to what is claimed, P1 or CC10 is not a specific and unique product of the lung, but like its homologue in rabbits (uteroglobulin) it is also present in urogenital secretions. P1 or CC10 may act as a natural immunosuppressor protecting the respiratory and urogenital tracts from unwanted inflammatory reactions.

Hypertension due to a renal renin-secreting tumour.

We report a case of a 25 year old man referred to our department because of a blood pressure of 162/122 mmHg, found during a general physical examination. A renal renin-secreting tumour was found to be the cause of the hypertension. It had a diameter of 4 cm and was enucleated from the right kidney. Subsequently the blood pressure returned to normal levels. Histological examination revealed a hemangiopericytoma.

Low-level lead exposure and blood pressure.

The possible association between low-level lead exposure and blood pressure (BP) remains debated. The purpose of this review was: (1) to determine whether the available studies in humans support a positive association, in particular at lower exposure levels (blood lead concentration < 1 mumol/l), and (2) to explore whether animal studies and the proposed pathophysiological mechanisms are supportive of a positive and causal association between lead exposure and hypertension. A meta-analysis of 23 studies included 33,141 subjects recruited from the general population in 13 surveys and from occupational groups in 10 studies. In all but four studies the results had been adjusted for age, and most studies also considered additional confounders. The association between BP and blood lead was similar in both sexes. In all 23 studies combined, a two-fold increase in blood lead concentration was associated with a 1 mm Hg rise in the systolic pressure (CI 0.4-1.6 mm Hg; P = 0.002) and with a 0.6 mm Hg increase in the diastolic pressure (CI 0.2-1.0 mm Hg; P = 0.02). Of 21 animal studies, one was carried out in dogs, one in pigeons and the remainder in various rat strains. In 15 studies, in which the lead dose in drinking water or food exceeded 1 p.p.m. the association between BP and exposure was found to be positive in seven, inconsistent in three, absent in four and negative in one. Of the six studies at lower exposure levels (< or = 1 p.p.m.), five found a pressor effect attributable to lead. Whether the lead doses in the animal studies are equivalent to the human exposure levels and to what extent one can extrapolate from genetically heterogeneous animals to humans, remains doubtful. If a causal relation between lead exposure and hypertension exists, the proposed mechanisms may include interference of lead with ion transport across cell membranes, interactions with calcium homeostasis and calcium-mediated processes, direct vasomotor actions and the potentiation of sympathetic stimulation. Interference of lead with the balance between the renin-angiotensin-aldosterone and the kallikrein-kinin systems and impairment of renal function are unlikely to be implicated. On balance, the published evidence suggests that there can only be a weak positive association between BP and lead exposure. The latter relation, which is barely visible at the horizon of epidemiological observation, may not be causal in nature and is unlikely to entail any public health implication in terms of hypertension-related complications.