Young Brains on Lead: Adult Neurological Consequences?

Abstract

Gilbert and colleagues examine the effect of chronic lowlevel lead exposure, occurring during development, on hippocampal neurogenesis and spatial learning in adulthood. The effects of lead exposure on cognitive and behavioral deficits in children leading to learning and memory impairments is well established, whereas there is little information on the long-term (adult) consequences of gestationally initiated lead exposure. One important issue that Gilbert and colleagues assess is the long-term consequences of chronic developmental low-level lead exposure in adult offspring. Secondly, Gilbert and colleagues are the first to report the effect of lead exposure on hippocampal neurogenesis. The work by Gilbert and colleagues is intriguing, in view of the fact that this paper attempts to integrate the consequences of developmental exposure to lead, known for its ability to impair cognitive functions, such as learning and memory, with a dysfunction in adult hippocampal neurogenesis. Chronic lead exposure initiated during development and continuing through adulthood (E16–PND75) resulted in a reduced survival of newly generated neurons in the dentate gyrus, but no effects on spatial learning and memory as assessed by the Morris water maze (MWM). As in other studies, discontinuation of lead at weaning did not result in observable differences from control animals in the chosen endpoint. Generally, the effects of developmental lead exposure on neurobehavioral deficits may or may not persist, and may be subtly manifested, but this paper emphasizes that lead exposure does have neurological consequences in the long term. Up until the early 1900s, lead poisoning was viewed largely as a disease of adults due to occupational exposure. However, the particular sensitivity of children to lead exposure quickly became recognized. In combination with higher rates of gastrointestinal tract absorption, the nervous systems of children are more vulnerable to the toxic effects of lead, making childhood exposure a great concern. Thus, much effort has been put into public awareness campaigns and government interventions to reduce the level of this environmental toxicant. Although mean national blood lead levels have decreased dramatically over the past 30 years in the United States, elevated levels are still found in specific areas, affecting mainly low-income, urban children and those living in older housing (Meyer et al., 2005). The most significant sources of lead continue to be old paint in homes built before 1978, lead pipes placed before the 1930s, and soil along highways and heavily traveled roads. A bimodal distribution of elevated blood lead levels in humans shows a peak for children (1–5 years of age) and a second one for adults >50 years of age (Pirkle et al., 1998). Therefore, despite intensive efforts to reduce lead use, exposure continues to be a major public health problem. Due to lead’s effects on children, the major focus of the literature has been on the acute effects of lead exposure in developing animals. Although there is considerable consensus about the toxic effects of high levels of lead, the effects of lowlevel lead exposure are less clear. Human epidemiological studies have consistently found a strong association between lead and IQ. However, there is still considerable debate on these manifestations, due to highly confounding variables such as socioeconomic status and quality of parenting. Animal studies have confirmed a significant interaction between developmental lead exposure and the nature and persistence of neurotoxic effects manifested in cognitive defects such as learning and memory, although these effects are highly ageand dose-dependent (Finkelstein et al., 1998). Numerous investigations focusing on the mechanism of lead neurotoxicity have found a wide array of effects, including apoptosis, excitotoxicity, interference with neurotransmitter storage and release mechanisms, alterations in second messengers, and damage to mitochondria (Lidsky and Schneider, 2003). Although there is no unifying mechanism, lead’s ability to substitute for calcium, and possibly zinc, is a factor common to many of its toxic actions. The disruption of dopaminergic functioning, which is involved in motor control and attention, as well as memory and executive functioning, can produce a host of behavioral problems, including attention deficit hyperactivity disorder and alterations in cognition (Brown et al., 1997). Also, lead has effects on glutamatergic transmission, which is a major player in both development and 1 To whom correspondence should be addressed. E-mail: bolivar@ wadsworth.org.