Sex-Dependent Effects of Developmental Lead Exposure on the Brain

Abstract

The role of sex as an effect modifier of developmental lead (Pb) exposure has until recently received little attention. Lead exposure in early life can affect brain development with persisting influences on cognitive and behavioral functioning, as well as, elevated risks for developing a variety of diseases and disorders in later life. Although both sexes are affected by Pb exposure, the incidence, manifestation, and severity of outcomes appears to differ in males and females. Results from epidemiologic and animal studies indicate significant effect modification by sex, however, the results are not consistent across studies. Unfortunately, only a limited number of human epidemiological studies have included both sexes in independent outcome analyses limiting our ability to draw definitive conclusions regarding sex-differentiated outcomes. Additionally, due to various methodological differences across studies, there is still not a good mechanistic understanding of the molecular effects of lead on the brain and the factors that influence differential responses to Pb based on sex. In this review, focused on prenatal and postnatal Pb exposures in humans and animal models, we discuss current literature supporting sex differences in outcomes in response to Pb exposure and explore some of the ideas regarding potential molecular mechanisms that may contribute to sex-related differences in outcomes from developmental Pb exposure. The sex-dependent variability in outcomes from developmental Pb exposure may arise from a combination of complex factors, including, but not limited to, intrinsic sex-specific molecular/genetic mechanisms and external risk factors including sex-specific responses to environmental stressors which may act through shared epigenetic pathways to influence the genome and behavioral output.

Keywords: brain; developmental exposure; epigenetics; gene; lead; neurotoxicity; prenatal stress; sex.

FIGURE 1

Altered sex specific transcriptome and methylome in response to Pb exposure in LE rats. Multi-dimensional scaling analysis of the gene expression response to lead (Reprinted from Schneider et al. (2011), with permission from Elsevier). Male and female groups occupy separate, diagonally opposite segments, indicating a significant sex-specific response that is in opposite directions in males and females.

FIGURE 2

Differential susceptibility to Pb exposure: Epigenome as a key player. Pb exposure causes alterations in epigenetic processes that regulate normal gene expression patterns and modulate the brain epigenome. These epigenetic mechanisms are also shared by various internal and external factors influencing the outcomes associated with Pb neurotoxicity. A better mechanistic understanding of Pb neurotoxic effects on each sex could come from investigating how the influences from external and internal factors during the lifetime converge upon the epigenetic platform leading to different outcomes.