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.

Sex-Dependent Effects of Developmental Lead Exposure in Wistar Rats: Evidence from Behavioral and Molecular Correlates

“…The present findings are consistent with studies in which Pb exposure through gestation and lactation led to impairment in learning and memory and depressive-like behavior in female but not male rats [36,43,45,46,[64][65][66]. We cannot rule out the possibility that adolescent rats could also be affected, as our longitudinal experimental design required the application of a battery of tests covering different behavioral domains knowingly sensitive to detect potential Pb-induced changes in age-specific abilities.…”

“…Overall, our behavioral and molecular data indicate more pronounced effects in females than males developmentally exposed to Pb, which by interfering with biochemical trajectories linked to the maturation of the excitatory circuits early in life may set the stage for behavioral alterations later in life. Of note, in epidemiological studies where sex effects were examined, adverse outcomes from developmental Pb exposures have been described more frequently in males than in females [35,36,90,91] in contrast to experimental findings. However, it has to be noted that the influence of sex/gender on outcomes may depend on the type of outcomes measured, the age of outcome assessment and, last but not least from the statistical methods applied.…”

“…Further studies are necessary to explore the hypothesis that Pb at environmentally relevant doses directly interferes with hormonal or neuroendocrine pathways. To date, being brain and behavior sexually dimorphic in mammals [85,86] it can be expected that molecular pathways implicated in complex behaviors, as well as epigenetic mechanisms, may be differentially modulated by exogenous stressors in the two sexes [36,66,82,[87][88][89]. Differences between sexes with regard to patterns of exposure, chemical absorption, and metabolism might be equally relevant and deserve specific attention in future experimental studies.…”

How early media exposure may affect cognitive function: A review of results from observations in humans and experiments in mice

“…The infant brain is very responsive to environmental changes. Many factors, such as early-life adverse events, pubertal and maternal stress (52)(53)(54), toxins (55)(56)(57), nutrition (58)(59)(60), geographic environment (61,62), and epigenetic factors (63,64), can have adverse consequences on neurodevelopment. Indeed, there is increasing evidence that most neurological and psychiatric disorders have a developmental origin that is the result of prenatal and early postnatal disturbances in this complex process (65)(66)(67)(68)(69).…”

In Utero Exposure to Aluminium and Other Neurotoxic Elements in Urban Coastal South African Women at Delivery: An Emerging Concern

“…Although both sexes are affected by Pb exposure, the incidence, manifestation, and severity of outcomes appear to differ. The sex-dependent variability in outcomes from Pb exposure during the developmental stages may arise from a combination of various influences such as intrinsic sex-specific molecular or genetic mechanisms and external risk factors like sex-specific responses to environmental stressors that may act through shared epigenetic pathways to influence the genome and behavioural output [65]. More research is needed; future studies should also include Al, given its involvement in neurotoxic and other health effects.…”