Prenatal Lead Levels, Plasma Amyloid [Beta] Levels, and Gene Expression in Young Adulthood

By Mazumdar, Maitreyi; Xia, Weiming et al. | Environmental Health Perspectives, May 2012 | Go to article overview

Prenatal Lead Levels, Plasma Amyloid [Beta] Levels, and Gene Expression in Young Adulthood


Mazumdar, Maitreyi, Xia, Weiming, Hofmann, Oliver, Gregas, Matthew, Ho Sui, Shannan, Hide, Winston, Yang, Ting, Needleman, Herbert L., Bellinger, David C., Environmental Health Perspectives


BACKGROUND; Animal studies suggest that early-life lead exposure influences gene expression and production of proteins associated with Alzheimer's disease (AD).

OBJECTIVES: We attempted to assess the relationship between early-life lead exposure and potential biomarkers for AD among young men and women. We also attempted to assess whether early-life lead exposure was associated with changes in expression of AD-related genes.

METHODS: We used sandwich enzyme-linked immunosorbent assays (ELISA) to measure plasma concentrations of amyloid [beta] proteins A[[beta].sub.40] and A[[beta].sub.42] among 55 adults who had participated as newborns and young children in a prospective cohort study of the effects of lead exposure on development. We used RNA microarray techniques to analyze gene expression.

RESULTS: Mean plasma A[[beta].sub.42] concentrations were lower among 13 participants with high umbilical cord blood lead concentrations ([greater than or equal to] 10 [micro]g/dL) than in 42 participants with lower cord blood lead concentrations (p = 0.08). Among 10 participants with high prenatal lead exposure, we found evidence of an inverse relationship between umbilical cord lead concentration and expression of ADAM metallopeptidase domain 9 (ADAM9), reticulon 4 (RTN4), and low-density lipoprotein receptor-related protein associated protein I (LRPAP1) genes, whose products are believed to affect A[beta] production and deposition. Gene network analysis suggested enrichment in gene sets involved in nerve growth and general cell development.

CONCLUSIONS: Data from our exploratory study suggest that prenatal lead exposure may influence A[beta]-related biological pathways that have been implicated in AD onset. Gene network analysis identified further candidates to study the mechanisms of developmental lead neurotoxicity.

KEY WORDS: Alzheimer's disease, children, fetal basis of adult disease, human, lead. Environ Health Perspect 120:702-707 (2012). http://dx.doi.org/10.1289/ehp.1104474 [Online 7 February 2012]

The weight of evidence supports an association between early-life exposure to lead and impaired cognitive function in children (Bellinger 2004; Lanphear et al. 2005.; Needleman 2004). Even at low levels, childhood lead exposure results in cognitive dysfunction that persists into adulthood (Mazumdar et al. 2011). In older adults, chronic environmental exposure to lead is associated with accelerated cognitive decline (van Wijngaarden et al. 2009; Weisskopf et at 2004, 2007; Weuve et al. 2009; Wright et al. 2003). Whether early exposure to lead has latent effects that contribute to neurodegenerative disease in old age is unknown.

Barker and Osmond (1986) demonstrated an .inverse relationship between birth weight and the incidence of cardiovascular disease. The Barker hypothesis, also known as the fetal basis of adult disease (FeBAD) hypothesis, states that many adult diseases have a fetal origin (Barker 1995). According to FeBAD, injury occurring at a critical period of development could result in changes in gene expression or gene imprinting, leading to deficits that become apparent later in life.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that results in dementia and death. The two classical lesions of AD are a) neuritic plaques containing extracellular deposits of the amyloid [beta] (A[beta]) proteins and b) neurofibrillary tangles, which are bundles of paired, helically wound filaments inside neurons (Selkoe 2008). The leading hypothesis for AD pathogenesis suggests that accumulation of A[beta] in the brain is the primary influence driving its development (Hardy and Selkoe 2002). Animal and cell culture studies have shown that lead exposure affects A[beta] production (Gu et al. 2011; Huang et al. 2011).

Recent animal studies suggest the expression of AD-related genes is altered in rodents and primates exposed to lead as infants. …

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