Early chronic low-level lead exposure produces glomerular hypertrophy in young C57BL/6J mice

Early chronic lead exposure continues to pose serious health risks for children, particularly those living in lower socioeconomic environments. This study examined effects on developing glomeruli in young C57BL/6J mice exposed to low (30 ppm), higher (330 ppm) or no lead via dams’ drinking water from birth to sacrifice on post-natal day 28. Low-level lead exposed mice [BLL mean (SD); 3.19 (0.70) μg/dL] had an increase in glomerular volume but no change in podocyte number compared to control mice [0.03 (0.01) μg/dL]. Higher-level lead exposed mice [14.68 (2.74) μg/dL] had no change in either glomerular volume or podocyte number. The increase in glomerular volume was explained by increases in glomerular capillary and mesangial volumes with no change in podocyte volume. Early chronic lead exposure yielding very low blood lead levels alters glomerular development in pre-adolescent animals

Statistical modeling with litter as a random effect in mixed models to manage “intralitter likeness”

© 2020 Elsevier Inc. “Intralitter likeness,” the possibility that the shared genetics and/or maternal environment in multiparous species causes strong similarity for outcome variables in littermates, violates a core statistical assumption, that of observation independence, when littermate outcomes are analyzed. Intralitter likeness has been of major concern to investigators for several decades. Despite consensus and guidance, many research reports in the rodent literature continue to ignore intralitter likeness. A historical review of the literature revealed that the long-preferred solution was to include litter as an effect in statistical models. Limitations in software development and computing capacity prior to 1990, however, appear to have led researchers and guidance authorities to endorse instead the method of using one value per litter. Here, the history of discussions regarding intralitter likeness in developmental neurotoxicological research is reviewed; growing knowledge regarding the biological bases and significance of intralitter likeness is discussed; principles underlying the use of litter as a random effect in mixed models are presented; statistical examples are provided illustrating the advantages and critical importance of including litter as a random effect in mixed models; and results using all data points (all pups from all litters) with litter as a random effect, are compared to results based on random selections of representative littermates. Mixed models with litter included as a random effect have distinct advantages for the analysis of clustered data. Modern computing capacity provides ready accessibility to mixed models for all researchers. Accessibility however does not preclude the need for appropriate expertise and consultation in the use of mixed (hierarchical) models

Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice

Research has suggested that chronic low‐level lead exposure diminishes neurocognitive function in children. Tests that are sensitive to behavioral effects at lowest levels of lead exposure are needed for the development of animal models. In this study we investigated the effects of chronic low‐level lead exposure on exploratory activity (unbaited nose poke task), exploratory ambulation (open field task) and motor coordination (Rotarod task) in pre‐adolescent mice. C57BL/6J pups were exposed to 0 ppm (controls), 30 ppm (low‐dose) or 230 ppm (high‐dose) lead acetate via dams’ drinking water administered from birth to postnatal day 28, to achieve a range of blood lead levels (BLLs) from not detectable to 14.84 µg dl–1). At postnatal day 28, mice completed behavioral testing and were killed (n = 61). BLLs were determined by inductively coupled plasma mass spectrometry. The effects of lead exposure on behavior were tested using generalized linear mixed model analyses with BLL, sex and the interaction as fixed effects, and litter as the random effect. BLL predicted decreased exploratory activity and no threshold of effect was apparent. As BLL increased, nose pokes decreased. The C57BL/6J mouse is a useful model for examining effects of early chronic low‐level lead exposure on behavior. In the C57BL/6J mouse, the unbaited nose poke task is sensitive to the effects of early chronic low‐level lead exposure. This is the first animal study to show behavioral effects in pre‐adolescent lead‐exposed mice with BLL below 5 µg dl–1. Copyright © 2014 John Wiley & Sons, Ltd

Polymorphisms of delta-aminolevulinic acid dehydratase (ALAD) and peptide tansporter 2 (PEPT2) genes in children with low- level lead exposure

Low-level lead exposure during early childhood has long been associated with altered neurocognitive development and diminished cognitive functions. Over nine thousand U.S. industrial facilities annually emit significant amounts of lead, creating exposure risk particularly for minority children. The mechanisms by which low-level lead exerts neurotoxic effects are poorly understood. Once absorbed, the only intervention is source removal, thus primary prevention is key. Genetic biomarkers could provide an efficient means of identifying children at greatest risk. Common functional variants of genes that alter lead\u27s neurotoxic potential have been identified and include delta-aminolevulinic acid dehydratase (ALAD(2)) and peptide transporter 2 (PEPT2*2). These polymorphisms have not been examined previously in Hispanic minority samples, or with regard to lowest level lead exposure. In 116 children of Mexican-American/Hispanic descent residing in zip codes previously designated as high risk for lead exposure (mean age=8.1, S.D.=1.9), blood lead level was measured at three time points over a 3-month period and averaged. DNA extraction was completed using buccal swab samples. The frequencies of the ALAD(2) and PEPT2*2 polymorphisms observed in this sample closely approximated those previously reported for Anglo, European and Asian samples. As compared to children heterozygous for the PEPT2*2 polymorphism, and without the PEPT2*2 polymorphism, the geometric mean blood lead level of children homozygous for the PEPT2*2 polymorphism was significantly higher. In contrast to past studies, mean blood lead level of children heterozygous and homozygous for the ALAD2 polymorphism in this sample did not differ from that of children without the ALAD2 polymorphism. Higher blood lead burden in children with the PEPT2*2 mutation may suggest that this common genetic variant is a biomarker of increased vulnerability to the neurotoxic effects of lowest level lead exposure

Early chronic low-level Pb exposure alters global exploratory behaviors but does not impair spatial and object memory retrieval in an object-in-place task in pre-adolescent C57BL/6J mice

© 2017 Elsevier Inc. The mechanisms by which early chronic low-level lead (Pb) exposure disrupts the developing brain are not yet understood. Rodent models have provided promising results however behavioral tests sensitive to effects at lowest levels of exposure during development are needed. Preadolescent animals (N = 52) exposed to low and higher levels of Pb via lactation from birth to PND 28 completed the Object-in-Place Task of visual spatial and visual object memory retrieval (at PND 28). Generalized linear mixed models were used, controlling for sex and litter as a random effect. As compared with controls, global vertical exploratory behavior (rearing) markedly increased during memory retrieval. The findings suggested that early chronic Pb exposure altered the development of critical exploratory functions needed for learning and survival. Behaviors exhibited in novel spatial and novel object zone perimeters suggested that the Object-in-Place task is a valid measure of visual spatial and visual object memory in pre-adolescent C57BL/6J mice. Additional studies are needed to understand how early chronic low-level lead exposure disrupts the trajectory and possible linkages of critical exploratory and perceptual systems during development