Manganese in the U.S. gasoline supply

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese compound recently approved for use in the United States as a gasoline additive. MMT use is expected to increase. This Commentary analyzes the impact of MMT use on population exposure to manganese, the health effects associated with manganese exposure, and the possibility that MMT use will lead to toxicity in the population. Although MMT use would result in only a small increment in most people's manganese exposure, certain populations will be disproportionately exposed. Although manganese is an essential nutrient at low levels, high-level manganese exposure leads to a characteristic severe nervous system toxicity. Pulmonary toxicity also occurs at high levels of exposure, and developmental toxicity to fetuses is an important concern based on more limited data. Selected subpopulations may be especially susceptible to the toxic effects of manganese. The critical question is whether the additional population exposure to manganese that would result from widespread MMT use would lead to toxic effects. Currently available evidence does not permit firm conclusions. Common sense and prudence therefore dictate that MMT not be used until further data are available and its safety is confirmed. Several measures are recommended to address the impending use of MMT in the U.S. gasoline supply. Am. J. Ind. Med. 31:107–115 © 1997 Wiley-Liss, Inc.     

镉对雄（男）性生殖系统毒性的研究进展

镉（Cadmium）是有毒重金属,其对肝、肾、肺、骨骼、生殖系统及血液系统均有毒性,雄性生殖系统对镉的毒性更加敏感。镉进入机体后抑制类固醇激素合成急性调节蛋白（steroidogenic acute regulatory protein,StAR）、胆固醇侧链裂解酶（P450scc）、3β-羟类固醇脱氢酶（3β-HSD）以及17β-HSD等睾酮合成关键酶活性,使睾酮合成受到抑制,血浆睾酮水平下降。镉可诱导生殖细胞凋亡,引起睾丸细胞和细胞器的超微结构变化,最终损害雄性生殖系统的功能。内分泌紊乱、氧化应激失衡和凋亡通路的激活在镉毒性机制中发挥着重要作用,某些抗氧化剂和抗凋亡药物可在一定程度上拮抗镉的生殖毒性。综述镉对雄（男）性生殖能力的影响和毒性机制。     

The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster

Background:

Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations.

Objectives:

Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure.

Methods:

To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs.

Results:

We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system.

Conclusions:

Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations.

Citation:

Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster. Environ Health Perspect 124:1062–1070; http://dx.doi.org/10.1289/ehp.1510513     

不同孕期铅暴露对大鼠妊娠结局及胎盘TIMP-1表达的影响

目的:观察孕期不同时段铅暴露对妊娠结局及胎盘TIMP-1表达的影响,探讨孕早期、孕后期及孕全程铅暴露的毒性特点及毒性机制。方法:采用原子吸收光谱仪测定孕期不同阶段低水平铅暴露后的大鼠孕末期血铅水平。0.025%醋酸铅对实验组孕鼠染毒,根据大鼠孕期3周推算足月剖宫产,观察异常分娩情况,记录胎盘质量、仔鼠数、仔鼠质量。免疫组化法测定胎盘滋养细胞TIMP-1的表达。结果:孕早期染铅对孕末期血铅水平及胎盘质量的影响较大,孕晚期染铅对仔鼠重量的影响较明显,孕全程染铅对孕末期血铅水平、胎盘质量及仔鼠质量均有明显影响。孕全程染铅组其胎盘TIMP-1表达最强。结论:铅具有生殖毒性及胚盘毒性,孕期不同时段铅暴露导致不同的妊娠结局。胎盘TIMP-1表达增强可能是铅致胎盘损伤的病理机制之一。     

儿童铅暴露临床资料分析及疗效观察

目的:观察铅暴露儿童主要症状、年龄特点、环境铅来源及锌钙制剂治疗前后血铅水平变化。方法:对2003年～2004年首都医科大学附属北京儿童医院就诊的43名铅暴露儿童诊治资料进行分析。铅暴露诊断参考指标为血铅大于5μg/dL,同时伴有症状者。资料分析包括:主要症状、血铅水平、环境铅源、年龄性别特点等。同时,对驱铅治疗前后血铅与血矿物元素等的变化进行评估。结果:血铅值在5～10μg/dl伴有临床症状的患儿占30.2%(13/43),男女儿童均在8～9岁时就诊率最高。膨化食品、玩具、碳酸饮料、房屋装修和咬铅笔是导致儿童铅暴露的高危因素,注意力涣散、易激惹和多动为最常见症状。用葡萄糖酸钙锌口服溶液躯铅治疗后,血铅值显示有意义下降(P<0.001),同时可防止血矿物元素的下滑。结论:神经症状出现在血铅水平<10μg/dl,说明铅损害可以发生在目前的诊断标准以下。铅损害的主要症状表现在神经系统。锌钙合剂治疗对降低血铅和恢复血钙、锌水平有较好效果。     

长期饮用纯净水对大鼠脏器及组织铅蓄积的影响

目的观察长期饮用纯净水是否能增加铅在体内的蓄积及毒性。方法将104只断乳雄性SPF级SD大鼠随机分为8组(其中铅染毒组经饮水途径给予醋酸铅),分别为自来水对照组、纯净水对照组、低铅自来水组(含铅50mg/L)、低铅纯净水组(含铅50mg/L)、中铅自来水组(含铅200mg/L)、中铅纯净水组(含铅200mg/L)、高铅自来水组(800mg/L)、高铅纯净水组(含铅800mg/L)。各组食物及其他处理因素完全一致。于第4、6、8、10、24、28周尾静脉采全血动态监测血铅,在28周时处死大鼠取材,采用原子吸收分光-石墨炉法测定血铅及脑、心脏、肝脏、肾脏、骨等实质性脏器及组织的铅含量;以表面荧光法检测血液锌原卟啉(ZPP)含量。结果在相同的铅染毒剂量下,不同的饮水对大鼠血铅的影响未显示统计学意义,但饮用纯净水的大鼠肾脏、心脏、肝脏、脑、骨中的铅含量均高于饮用自来水的大鼠;同时饮用纯净水的大鼠其血液锌原卟啉含量均高于饮用自来水的大鼠,在低剂量铅染毒组间差异有统计学意义(P<0.05)。结论在本研究的染毒剂量下,结果提示长期饮用纯净水能增加铅在大鼠心、肝、肾、脑、骨中的蓄积及其对造血系统的毒性,尤其是在低铅暴露背景下。     

铅锌联合作用对仔鼠学习记忆行为的影响

目的探索能拮抗铅毒性的锌剂量，为防制铅毒害提供理论依据。方法从妊娠期开始建立空白组、染铅组、不同剂量锌与铅联合作用的仔鼠模型，在仔鼠出生后21d测定鼠血锌、脑锌及血铅、脑铅，并用暗箱电击法进行行为学测试。结果锌可以降低血铅浓度，但却不能使脑铅浓度降低。铅可降低仔鼠的学习记忆能力，中等剂量及高剂量的锌能拮抗铅的作用，且此2组仔鼠学习记忆能力与空白对照组相比差异无显著性。结论中等剂量的锌可以拮抗铅的毒性。     

A case of mistaken identity: herbal medicine as a cause of lead toxicity.

Folk remedies can be a significant unrecognized source of lead toxicity. This case report of lead toxicity due to Indian traditional herbal medicine illustrates that suspecting only occupational sources for lead poisoning in adults may mask a true source of lead exposure.     

Prenatal lead acetate exposure induces apoptosis and changes GFAP expression during spinal cord development

Lead is an important heavy metal pollutant in the environment, and it induces neurodevelopmental toxicity, which is characterized by histological, ultrastructural, and neurochemical changes in the central nervous system. The aim of this study was to evaluate the effects of prenatal acute lead exposure on apoptosis, GFAP expression, and lead deposition in the developing spinal cord. Chick embryos were exposed to 150μg or 450μg doses of lead acetate via yolk sac at E3 or E5 embryonic ages and incubated for six days. Lead deposition was observed in the ependymal cells, developing dorsal, and ventral horns, and in the white matter of all the exposed embryos. TUNEL-positive cells were found in all layers of the spinal cord of the control and treated embryos, and lead exposure resulted in a significant increase in the numerical density of the apoptotic cells. Control embryos showed intense GFAP expression in the ependymal cells of the roof and floor plates, and in the gray and white matters; whereas exposure to lead reduced GFAP reactivity. In ovo lead exposure induces apoptosis, and reduces GFAP expression in the nervous system of the chick embryos, which may cause impairments during neuronal development and consequences in childhood and adulthood.     

Environmental lead toxicity and nutritional factors

Environmental lead toxicity is an old but persistent public health problem throughout the world and children are more susceptible to lead than adults because of their hand to mouth activity, increased respiratory rates and higher gastrointestinal absorption per unit body weight. In the last decade children's blood lead levels have fallen significantly in a number of countries. Despite this reduction, childhood lead toxicity continues to be a major public health problem for certain at-risk groups of children, and concern remains over the effects of lead on intellectual development. The currently approved clinical intervention method is to give chelating agents, which bind and removed lead from lead burdened tissues. Studies indicate, however, that there is a lack of safety and efficacy when conventional chelating agents are used. Several studies are underway to determine the beneficial effect of nutrients supplementation following exposure to lead. Data suggest that nutrients may play an important role in abating some toxic effects of lead. To explain the importance of using exogenous nutrients in treating environmental lead toxicity the following topics are addressed: (i) different sources of lead exposure/current blood lead levels and (ii) protective effects of nutrients supplementation (some essential elements and vitamins) in lead toxicity.     

Occupational lead exposure and women

The toxicity of lead has been known for approximately 2000 years, but the issue of women exposed to lead in the workplace has received relatively little attention until recent years. The major thesis of this paper is that the fetus represents an organism which is sensitive to lead and that the fetus is exposed to lead through the mother by the fact that lead crosses the placental barrier. Fetal exposure to lead is, in the author's opinion, the critical issue involved in assessing occupational exposure to lead among women of childbearing age. Multiple studies have demonstrated that concentrations of lead in the mother's blood are comparable to concentrations of lead in umbilical cord blood at birth. Many investigators consider the demonstrated effects of lead upon the hematopoietic system to be the earliest effect associated with lead exposure. Control strategies which prevent significant alterations in the heme synthetic pathway of the mother should prevent such changes in the fetus and thus protect against the more serious adverse effects of fetal lead exposure.     

The interaction of lead exposure and pregnancy.

The toxic effects of low-level lead exposure have been the subject of a good deal of research and media attention in recent times. In most countries, the acceptable occupational exposure limit for lead is being progressively decreased as the adverse health effects of lead are being identified at levels approaching those found in non-occupational environments. Due to the sensitive nature of the fetus to hazardous substances, the exposure to lead of the unborn child via maternal sources is of critical concern. Preterm delivery, congenital abnormalities and decreases in growth stature have all been associated with prenatal lead exposure at "acceptable" levels. There is an accumulation of evidence which indicates that maternal exposures prior to conception can play an important role in determining blood lead levels during pregnancy. In light of these observations the practice of removing the pregnant woman from lead sources may be of questionable value with regards to providing sufficient protection for the fetus. This article reviews the relevant literature pertaining to the mobilization of lead from bone during pregnancy and the toxicity of low-level lead exposure to the fetus, and briefly discusses some factors which may affect this toxicity.     

Lead toxicity in the shipbreaking industry: the Ontario experience

Lead exposure occurs during ship demolition when the ship structure has been previously coated with lead-based paint. An investigation and follow-up of employee lead exposure at the 4 shipbreaking operations in Southern Ontario revealed widespread excessive lead exposure. Air sampling results for lead were above the Ontario standard at all locations. 34 of 113 workers (30%) had at least one blood lead above 3.4 mumol/L*; 50% of workers at one company had results above 2.5 mumol/L. At these blood levels, neurologic, renal and hematologic effects may develop. Institution of control measures (appropriate respirators and hygiene practices, worker education and training, prompt employee notification of blood lead levels) reduced employee lead exposure and lowered blood lead results. Continued vigilance and ongoing employee education and training are required to prevent lead toxicity in shipbreaking. *70 micrograms/100 ml = 3.4 mumol/L.     

Lead poisoning--one approach to a problem that won't go away.

A reduction in sources of environmental lead exposure has resulted in substantial declines in mean blood lead concentrations of all age groups in the United States. However, some segments of the population continue to have unacceptable levels of lead exposure and elevated blood lead concentrations. In addition, virtually all residents of industrialized countries have bone lead stores that are several orders of magnitude greater than those of our preindustrial ancestors. Recent studies suggest that these skeletal lead stores adversely affect health and can contribute to reduced birth weights, aggressive behavior in children, and anemia, hypertension, and kidney disease in adults. Evidence is described that demonstrates that an increase in dietary calcium consumption can reduce lead absorption and toxicity from exogenous and endogenous lead exposure. A relatively inexpensive and effective way to reduce the substantial morbidity that will result from widespread lead exposure is by fortification of a variety of foods with low levels of calcium. This approach can complement other efforts to prevent lead exposure and reduce lead toxicity.     

Lead exposure in female workers who are pregnant or of childbearing age

In adults, high-level lead exposure often occurs in the lead-related industries. Acute lead poisoning has become rare, but chronic exposure to low-level lead remains a public health issue. With recent advances in our understanding of lead toxicity at low-levels, researchers have shifted their focus to studying lead at concentrations below those currently recommended as 'acceptable' in worker protection. As gender plays an important role in the storage, biokinetics, and toxicity of lead, it seems inappropriate to extrapolate findings of lead exposure in men to women. Women's bones release lead more slowly to the bloodstream, so blood levels remain increased for a long time after cessation of high exposure, reflecting the endogenous source of the lead. Particularly in pregnant women, bone lead release could influence health in pregnancy and be extremely harmful to the rapidly growing and developing fetus. Accordingly, female workers of childbearing age should avoid excessive lead exposure. However, because studies of pregnant workers encounter many difficulties and inconveniences, sufficient research has not been conducted in this area. As an alternative, a group of non-occupationally exposed women, matched as well as possible for anthropometric and reproductive variables and with almost the same levels of blood lead, could be recruited for survey.     

Effects of lead on immune parameters in occupationally exposed workers

BACKGROUND: To assess the immune competence of workers occupationally exposed to lead, several subsets of peripheral lymphocytes, i.e., T, TCD4(+), TCD8(+), B, NK cells, serum immunoglobulin and complement protein concentrations, chemotaxis, and intracellular killing activity of neutrophils of 25 male storage battery workers have been analyzed and compared to 25 healthy males with no history of lead exposure. RESULTS: The results of this study which indicated that industrial exposure to lead resulting in group mean blood lead concentrations of 75 +/- 18 microg/dl are associated with a significant depression of: T helper lymphocytes, Ig G, Ig M and C3, C4 complement levels, chemotaxis, and random migration of neutrophils. No correlation was found between the duration of exposure and the altered immune parameters. CONCLUSIONS: The immune system can be a target for lead toxicity and elimination of lead hazard in working places is necessary.     

RNA/DNA ratios as a sublethal endpoint for large-scale toxicity tests with the nematode Caenorhabditis elegans

Caenorhabditis elegans increasingly is attractive as a toxicity test organism, particularly as a model system to study mechanisms of toxicity at a molecular level and the way that these lead to whole organism and population level effects. Inhibitions of growth, reproduction, movement, and feeding rate all have been proposed as sublethal toxicity endpoints. These endpoints are more sensitive than 24-h acute toxicity endpoints, but assays are much more time consuming, making them difficult to use in mass screening. The RNA/DNA ratio, after 48-h exposure to metals, has median effective concentration (EC50) values of 0.05, 0.6, 6.1, and 35 mg/L for Cu, Pb, Cd, and Zn, respectively. This makes it a slightly more sensitive toxicity endpoint than reduction of individual growth after 72-h exposure to the same concentrations. This facilitates the near-simultaneous assessment of sublethal toxicity in many nematode samples. The constant cell number of C. elegans means that different stages in the life history have very different RNA/DNA ratios even in the absence of toxins. So, RNA/DNA ratios can be used only on prereproductive, age-synchronized cultures. Assessing the sublethal toxicity of metals to C. elegans shows that it is sensitive particularly to Cu.     

铅和乙醇对雄性大鼠生殖系统的联合毒作用

采用整体动物实验方法,观察铅和乙醇对大鼠精子数量和质量,以及血中性激素水平的联合作用。结果显示,精子计数联合组比铅和乙醇单独作用组显著减少;精子活动度分析联合组与其他各组比较显著下降。铅和乙醇单独作用均可使雄性大鼠血清睾酮(T)升高,促黄体生成激素(LH)下降,联合作用使T降低,LH较单独作用组升高。提示铅和乙醇联合染毒对雄性大鼠生殖毒性影响可能具有增毒作用。     

母鼠铅染毒对仔鼠生理发育与行为能力的影响及其与锌的相互作用

目的 研究孕期铅染毒对仔鼠生理发育与行为能力的影响及其与锌的相互作用。方法 给孕期母鼠喂饲含有铅、锌及铅加锌的水，观察母鼠孕期体重变化及仔鼠成活率和体重变化；采用动物行为学观察方法测试并评价其子代鼠生理发育及行为学能力，并对仔鼠脑组织单胺类神经递质及脂质过氧化产物丙二醛（MDA）含量进行了检测。结果 在未对母鼠孕期体重增大产生不良影响的铅、锌剂量下，孕期铅染毒可降低仔鼠成活率，抑制仔鼠体重增长，延迟仔鼠生理发育及新生反射发育的同时，仔鼠脑组织单胺类神经递质合成与代谢紊乱，MDA含量明显增加，母鼠孕期给锌对仔鼠成活率、体重增长未见明显物保护作用。等摩尔锌对仔鼠新生反射发育有明显的干预效果，锌还可抑制铅所致仔鼠脑组织MDA含量增加的作用。铅染毒同时给半量的锌反而使其仔鼠生理发育时间有明显的延迟作用，并促进多巴胺和5-羧色胺分解。结论 孕期铅染毒对仔鼠生理发育与行为能力有不良的影响，锌的浓度不同所表现的联合作用类型也不同，锌与铅的相互作用是十分复杂的，利用锌拮抗铅的神经毒作用时，应持慎重态度。     

Lead exposure in a firing range.

We report lead exposure in four employees of a privately owned shooting range, one of whom had neurological toxicity due to lead. Increasing time worked at the range was associated with elevation of blood lead. This incident emphasizes the risk of airborne lead exposure to employees of firing ranges.