DNA damage and repair in cells of lead exposed people

Restrepo, Helena Groot de; Sicard, Diana; Torres, María Mercedes

doi:10.1002/1097-0274(200009)38:3<330::aid-ajim13>3.0.co;2-z

Cited by 57 publications

(23 citation statements)

References 9 publications

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“…While some studies have reported an increase in single‐strand breaks (SSBs) in peripheral lymphocytes of humans occupationally exposed to high levels of lead [40–43], other studies have detected no increase in SSBs associated with lead exposure [44,45]. As a potential explanation for this discrepancy, we offer the following.…”

Section: Discussionmentioning

confidence: 84%

Lead promotes abasic site accumulation and co‐mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1

McNeill

Wong

Narayana

et al. 2006

Molecular Carcinogenesis

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Lead is a widespread environmental toxin, found in contaminated water sources, household paints, and certain occupational settings. Classified as a probable carcinogen by the International Agency for Research on Cancer (IARC), lead promotes mutagenesis when combined with alkylating and oxidizing DNA-damaging agents. We previously reported that lead inhibits the in vitro repair activity of Ape1, the major endonuclease for repairing mutagenic and cytotoxic abasic sites in DNA. We investigated here whether lead targets Ape1 in cultured mammalian cells. We report a concentration-dependent inhibition of apurinic/apyrimidinic (AP) site incision activity of Chinese hamster ovary (CHO) AA8 whole cell extracts by lead. In addition, lead exposure results in a concentration-dependent accumulation of AP sites in the genomic DNA of AA8 cells. An increase in the oxidative base lesion 8-oxoguanine was observed only at high lead levels (500 microM), suggesting that non-specific oxidation plays little role in the production of lead-related AP lesions at physiological metal concentrations--a conclusion corroborated by "thiobarbituric acid reactive substances" assays. Notably, Ape1 overexpression in AA8 (hApe1-3 cell line) abrogated the lead-dependent increase in AP site steady-state levels. Moreover, lead functioned cooperatively to promote a further increase in abasic sites with agents known to generate AP sites in DNA (i.e., methyl methansulfonate (MMS) and hydrogen peroxide (H2O2), but not the DNA crosslinking agent mitomycin C. Hypoxanthine guanine phosphoribosyltransferase (hprt) mutation analysis revealed that, whereas lead alone had no effect on mutation frequencies, mutagenesis increased in MMS treated, and to a greater extent lead/MMS treated, AA8 cells. With the hApe1-3 cell line, the number of mutant colonies in all treatment groups was found to be equal to that of the background level, indicating that Ape1 overexpression reverses MMS- and lead-associated hprt mutagenesis. Our studies in total indicate that Ape1 is a member of an emerging group of DNA surveillance proteins that are inhibited by environmental heavy metals, and suggest an underlying mechanism by which lead promotes co-carcinogenesis.

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Section: Discussionmentioning

confidence: 84%

Lead promotes abasic site accumulation and co‐mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1

McNeill

Wong

Narayana

et al. 2006

Molecular Carcinogenesis

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“…Most studies of lead-exposed human populations report chromosomal toxicity and interference with repair of DNA damage 118, 119 leading to increased in vitro mutagenicity 120. Despite limitations with exposure assessment, the direction of risk in most cohort studies of lead exposure has been positive 121.…”

Section: Risk Factorsmentioning

confidence: 99%

Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium

Bondy

Scheurer

Malmer

et al. 2008

Cancer

778

614

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Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the group's consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address.

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“…Although a sustained and sizeable decrease in human body Pb burden has been observed at the same time (Gottlieb, 1998), scientific interest and concerns among public health researchers and epidemiologists over the long-term negative potential of Pb contamination have not abated. In particular, attention has focused on reproductive, genotoxic, carcinogenic, and neurological effects (Fu and Boffetta, 1995;Apostoli et al, 2000;Hertz-Picciotto, 2000;Lorente et al, 2000;Ojajarvi et al, 2000;Pesch et al, 2000;Restrepo et al, 2000;Schwartz et al, 2000;Silbergeld et al, 2000). For these reasons, populations exposed to environmental Pb deserve to be monitored in order to detect early reversible abnormalities and lifethreatening disorders and, as a corollary result, to improve the scientific knowledge on the biological impairments attributable to Pb burdens.…”

Section: Introductionmentioning

confidence: 99%

Adverse haematological outcome and environmental lead poisoning

Fontana¹,

Baldi

Franchini

et al. 2004

J Expo Sci Environ Epidemiol

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The South-eastern Area (SA) of the Municipality of La Spezia (Liguria Region, Italy) is characterised by a heavy environmental lead (Pb) contamination, chiefly due to the emissions of a Pb-processing plant in operation since 1930. In order to assess the risk of Pb poisoning of residents of SA, and to estimate the degree of association between the blood Pb level (BLL) and haematocrit % (HCT), intended as a biomarker of early haematological dysfunction, we reanalysed data of 785 individuals collected in 1992 as a part of a larger national biological monitoring project. Multiple normal regression modelling was applied to estimate the role of residence on log-transformed BLL, and Median Ratio (MR) was used as an index of effect. The same statistical modelling was also applied to reveal the relationship between HCT and BLL. Allowing for several confounders (including occupational exposure to Pb), residents of SA showed a 14% increase (MR ¼ 1.14, 95% IC ¼ 1.06-1.23%) in the median BLL value compared to people living outside SA. The excess reached 27% (MR ¼ 1.27, 95% IC ¼ 1.14-1.41%) after 30 years of residence. Parallel results were also obtained in a subgroup composed only of pupils (o18 years, non-smokers, non-drinkers). Finally, regression analysis highlighted a statistically significant parabolic trend in HCT in relation to BLL. The non-linear dose-response relationship, which attests to an adverse effect on the erythrocytic function of BLLs at least over 17.00 mg/dl, is in agreement with the findings of other authors and consistent with the results of an excess occurrence of self-reported anaemia obtained from a previous comparative survey carried out on the same population.

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DNA damage and repair in cells of lead exposed people

Cited by 57 publications

References 9 publications

Lead promotes abasic site accumulation and co‐mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1

Lead promotes abasic site accumulation and co‐mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1

Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium

Adverse haematological outcome and environmental lead poisoning

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