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.

BACKGROUND:Inflammation is a major cause of preterm birth and often results in a fetal inflammatory response syndrome (FIRS). Preterm infants with FIRS have a higher childhood incidence of neurodevelopmental disability than preterm infants without FIRS. The mechanisms connecting FIRS to neurodevelopmental disability in formerly preterm infants are not fully understood, but the effect on premature gray matter may have an important role.METHODS:Fetal rats were exposed to intra-amniotic (i.a.) LPS two days prior to birth to model FIRS. On postnatal day 7, expression of inflammatory mediators was measured in the liver, lung and brain. Activation of microglia and expression of glutamatergic receptor subunits and transporters were measured in the hippocampus and cortex.RESULTS:LPS caused persistent systemic inflammatory mediators gene expression. In the brain, there was corresponding activation of microglia in the hippocampus and cortex. Expression of inflammatory mediators persisted in the hippocampus, but not the cortex, and was associated with altered glutamatergic receptor subunits and transporters.CONCLUSION:Hippocampal inflammation and dysregulation of glutamate metabolism persisted well into the postnatal period following i.a. LPS. Poor neurodevelopmental outcomes after FIRS in preterm infants may result in part through glutamatergically-driven gray matter injury to the neonatal hippocampus.

Background: Phlebotomy-induced anemia (PIA) is universal and variable in degree among preterm infants and may contribute to neurodevelopmental risk. In mice, PIA causes brain tissue hypoxia, iron deficiency, and long-term sex-dependent neurobehavioral abnormalities. The neuroregulatory molecular pathways disrupted by PIA underlying these effects are unknown. Methods: Male and female pups were phlebotomized daily from postnatal day (P)3-P14 via facial venipuncture to target hematocrits of 25% (moderate, mPIA) and 18% (severe, sPIA). P14 hippocampal RNA from non-bled control and PIA mice was sequenced by Next-Generation Sequencing to identify differentially-expressed-genes (DEGs) that were analyzed using Ingenuity Pathway Analysis. Results: mPIA females showed the least DEGs (0.5% of >22,000 genes) whereas sPIA females had the most (8.6%), indicating a dose-dependent effect. mPIA and sPIA males showed similar changes in gene expression (5.3% and 4.7%, respectively), indicating a threshold effect at mPIA. The pattern of altered genes induced by PIA indicate sex-specific and anemia-dose-dependent effects with increased pro-inflammation in females and decreased neurodevelopment in males. Conclusion: These gene-expression changes may underlie the reduced recognition memory function in male and abnormal social-cognitive behavior in female adult mice following neonatal PIA. These results parallel clinical studies demonstrating sex-specific behavioral outcomes as a function of neonatal anemia.

Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influence gene expression patterns and affect the function and development of the nervous system. The present promoter-based methylation microarray profiling study explored the extent to which developmental Pb exposure may modify the methylome of a brain region, hippocampus, known to be sensitive to the effects of Pb exposure. Male and female Long Evans rats were exposed to 0 ppm, 150 ppm, 375 ppm, or 750 ppm Pb through perinatal exposures (gestation through lactation), early postnatal exposures (birth through weaning), or long-term postnatal exposures (birth through postnatal day 55). Results showed a significant contribution of sex to the hippocampal methylome and effects of Pb exposure level, with non-linear dose response effects on methylation. Surprisingly, the developmental period of exposure contributed only a small amount of variance to the overall data and gene ontology (GO) analysis revealed the largest number of overrepresented GO terms in the groups with the lowest level of exposure. The highest number of significant differentially methylated regions was found in females exposed to Pb at the lowest exposure level. Our data reinforce the significant effect that low level Pb exposure may have on gene-specific DNA methylation patterns in brain and that this occurs in a sex-dependent manner.

While multiple factors contribute to this increased neurodevelopmental risk, the degree of neonatal anemia is one that is controllable by the healthcare team. However, two randomized trials that