Low-Level Human Equivalent Gestational Lead Exposure Produces Sex-Specific Motor and Coordination Abnormalities and Late-Onset Obesity in Year-Old Mice

Abstract

BackgroundLow-level developmental lead exposure is linked to cognitive and neurological disorders in children. However, the long-term effects of gestational lead exposure (GLE) have received little attention.ObjectivesOur goals were to establish a murine model of human equivalent GLE and to determine dose–response effects on body weight, motor functions, and dopamine neurochemistry in year-old offspring.MethodsWe exposed female C57BL/6 mice to water containing 0, 27 (low), 55 (moderate), or 109 ppm (high) of lead from 2 weeks prior to mating, throughout gestation, and until postnatal day 10 (PN10). Maternal and litter measures, blood lead concentrations ([BPb]), and body weights were obtained throughout the experiment. Locomotor behavior in the absence and presence of amphetamine, running wheel activity, rotarod test, and dopamine utilization were examined in year-old mice.ResultsPeak [BPb] were < 1, ≤ 10, 24–27, and 33–42 μg/dL in control, low-, moderate- and high-dose GLE groups at PN0–10, respectively. Year-old male but not female GLE mice exhibited late-onset obesity. Similarly, we observed male-specific decreased spontaneous motor activity, increased amphetamine-induced motor activity, and decreased rotarod performance in year-old GLE mice. Levels of dopamine and its major metabolite were altered in year-old male mice, although only forebrain utilization increased. GLE-induced alterations were consistently larger in low-dose GLE mice.ConclusionsOur novel results show that GLE produced permanent male-specific deficits. The nonmonotonic dose-dependent responses showed that low-level GLE produced the most adverse effects. These data reinforce the idea that lifetime measures of dose–response toxicant exposure should be a component of the neurotoxic risk assessment process.

Effects of low level lead exposure on associative learning and memory in the rat: Influences of sex and developmental timing of exposure

“…The results of the current study suggest that there are also complex effects of sex, developmental window of exposure and level of Pb-exposure on associative memory as assessed by trace fear conditioning. Similar to previous reports by us and others (Schneider et al, 2012a; Schneider et al, 2013); (Leasure et al, 2008), greater effects were observed at lower levels of Pb exposure in several of the experimental groups and in the present study, this was observed more frequently in females. This type of nonlinear dose-response effect of Pb is consistent with other work (e.g., Lanphear et al , 2005; Leasure et al , 2008) that suggested that the impact from exposure to low levels of Pb may be greater than the proportional impact from higher level exposures.…”

Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism

“…To determine the timing of Pb effects, these researchers exposed mice from 2 weeks prior to mating through PND10 or from PND0- 21. Similar to many of the rat studies reviewed above, this group found a non-monotonic dose response to Pb, with the largest Pb-induced alterations appearing in the low-dose mice [47]. Further, Leasure et al found that male mice exhibited late-onset obesity, decreased motor activity, and altered dopamine levels.…”

Perinatal Lead (Pb) Exposure Results in Sex-Specific Effects on Food Intake, Fat, Weight, and Insulin Response across the Murine Life-Course

“…Developmental exposure to the heavy metal lead (Pb) has been associated with decreased fetal and childhood growth, and risk of delayed puberty in humans [3]–[7] and early onset of puberty, and late onset obesity in rodents [8], [9]. Human studies of the association of Pb exposure with weight status are conflicting.…”