The Toxicologist - Society of Toxicology

doses causes physiological changes that increase the likelihood of diseases in adulthood
such as obesity, hypertension, and neurological disorders. Although human
epidemiological data also support an association between increased Pb exposure
and hypertension or cognitive impairment, the exact mechanisms by which lead exerts
these effects in epidemiologic studies is unknown. We will discuss experimental
animal toxicology data that suggest several possible mechanisms for developmental
origins of adult diseases (DOAD) associated with exposure to low levels of lead.
Data support a sex-dependent mechanism resulting in increased fat deposition and
late-onset obesity, retinal degeneration, and motor activity aberrations following
low dose gestational lead exposure in male mice. Lead-induced hypothalamic pituitary
adrenal axis dysfunction is a potential mechanism for a range of adult diseases
and disorders, including hypertension, diabetes, metabolic syndrome, schizophrenia,
and cognitive dysfunction. Epigenetic mechanisms have also been implicated,
and epigenetic pathways may present a mechanistic link between developmental
lead exposure and the etiology of Alzheimer’s disease. These data highlight the importance
of exposure windows for the development of adverse health effects associated
with low-level lead and have possible risk assessment implications for ongoing
assessments such as the NTP Monograph on Low-Level Lead and the U.S. EPA
Integrated Science Assessment for Lead.
1698 LOW-LEVEL GESTATIONAL LEAD EXPOSURE IS A
RISK FACTOR FOR LATE-ONSET METABOLIC
SYNDROME AND NEURODEGENERATION.
D. A. Fox. University of Houston, Houston, TX.
Obesity is a pandemic as 65% of adolescents and adults are overweight and 30%
are obese. Epidemiological studies show a positive association between developmental
lead exposure and increased body mass index (BMI) during adulthood.
Increased BMI also shows a significant inverse log-linear relationship with blood
[Pb] ([BPb]). There are several critical periods of nervous and immune system
growth and development during which toxicant exposure can increase susceptibility
to diseases later in life. To investigate the effects of low-level gestational lead exposure
(GLE) on late-onset metabolic and neurodegenerative, we developed a human
equivalent gestational lead exposure (GLE) model. Mice were exposed to three different
levels of lead during pregnancy until postnatal day 10 (PN10): period of rodent
brain/retinal development equivalent to that during human gestation. Peak
[BPb] for controls, low-, moderate- and high-level lead groups on PN10 were 90% of
AD cases, the differential susceptibility and course of illness, as well as the late age
onset of the disease suggests that epigenetic and environmental components play a
role in the etiology of LOAD. One of the first indications that epigenetics was involved
in LOAD came from studies from our lab (Basha et al., 2005; Wu et al.,
2008; Zawia et al., 2009) which showed that lead (Pb) exposure occurring during
brain development pre-determined the expression and regulation of AD-related
genes later in life, influencing the course of amyloidogenesis and oxidative DNA
damage via a process that involved DNA methylation. This presentation will focus
on the mechanisms by which early life exposure to Pb can modify DNA through
epigenetic pathways rendering DNA repair pathways ineffective in old age to
counter oxidative damage. The interaction between DNA methylation and DNA
oxidation and their relevance to Alzheimer’s disease will be discussed. In addition, a
global assessment of gene expression and DNA methylation across the lifespan of
developmentally exposed animals will be presented. The integration of global gene
expression profiles, with simultaneous consideration of both genetic and epigenetic
characteristics and of the interactions between these factors and aging, will shed
some light on the complex pathobiology of neurodegeneration.
1701 CONTRASTING THE DEVELOPMENTAL AND ADULT
ORIGINS OF ADVERSE EFFECTS FROM LEAD IN THE
DRAFT NTP MONOGRAPH ON LOW-LEVEL LEAD.
A. A. Rooney. Center for the Evaluation of Risks to Human Reproduction, NIEHS,
National Toxicology Program, Research Triangle Park, NC.
Epidemiological evidence supports a broad range of effects associated with elevated
blood lead (Pb) levels including neurological, cardiovascular, renal, immune, reproductive
and developmental effects. Children are regarded as particularly vulnerable
to Pb due to exposure issues leading to higher blood Pb levels in children as well as
data suggesting that children are more sensitive to some of the health effects associated
with Pb exposure. In particular, numerous studies report impaired cognitive
function associated with developmental or childhood exposure to Pb at blood lead
levels < 10 micrograms/dL, whereas effects on cognitive function in adults are generally
associated with higher blood Pb levels. Immunological studies also suggest
that early development may be a period of greater susceptibility to Pb as several epidemiological
studies report an association between developmental exposures to Pb
at low levels with elevated serum IgE. The increased production of IgE suggests a
mechanism by which Pb may contribute to the development of allergic asthma and
later life allergic disease. For other endpoints, such as reduced renal function, increased
blood pressure and hypertension, the deleterious effects associated with low
blood Pb levels in adults are well established; however, fewer studies address the impact
of developmental exposure. The NTP Center for the Evaluation of Risks to
Human Reproduction is developing an NTP Monograph on Low-Level Pb that
will evaluate the scientific evidence regarding the potential health effects associated
with low exposure levels of lead (i.e., blood Pb levels < 10 micrograms/dL). The examples
listed above illustrate the importance of exposure timing for the development
of some Pb-related adverse health effects, a factor that will be considered in
the NTP’s evaluation of low-level Pb.