Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure

Abstract

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.

Sex-Dependent Impact of Low-Level Lead Exposure during Prenatal Period on Child Psychomotor Functions

“…Increasing evidence points to sex differences in epigenetic mechanisms: DNA methylation profiles in brain can be modified by hormonal influences [ 42 , 43 , 44 , 45 , 46 ]. A recent study by Singh et al (2018) found that rats exposed to different lead doses, during different developmental windows, displayed significant alterations of methylation profiles in genes functionally relevant to brain development, notably, the lead-induced changes of DNA methylation in the hippocampus were markedly sex-dependent [ 47 ]. These findings are consistent with the result of a research performed in peripheral blood samples from children of both sexes, where lead-associated changes in DNA methylation showed a significant sex dimorphism [ 48 ].…”

Epigenetics and Lead Neurotoxicity

“…The relations of lead exposure with neural epigenetic alterations have long been established. Developmental lead exposure results in a variety of epigenetic changes, characterized by DNA methylation alterations, which can impact gene expression patterns and affect nervous system development [5]. Lead can promptly affect the dynamism of epigenetic determinants and promote the rapid turnover of DNA methylation [4].…”

“…Lead exposure can result in the global changes of DNA methylation profiles in CNS, and the detailed orientation of methylome changes varied depending on the studied genetic microenvironment. Singh et al stated that developmental lead exposure disrupted the hippocampal methylome, and the effect is dependent on the gender, timing, and level of exposure [5]. In particular, the global methylome alterations did not reflect the methylation status of the specific genes.…”

“…But this association was dependent on gender, the exposure periods, and their relative genetic locations. Interestingly, for females, genes regulated by DNA methylation were inclined to encode RNA-and protein-related processes; and for males, the enriched pathways included signaling pathways, stress, and neural responses to stimuli [5].…”

“…Although lead has been removed from paints and gasoline, it remains a serious concern as it can still be found in a variety of daily products, including toys, batteries, food, and water [2]. Although Pb poisoning is a preventable disease, thousands of new cases in the United States were reported each year, and about 500,000 children under 5 years old have blood lead levels (BLLs) greater than a threshold level of 5 g/dl, according to Centers for Disease Control and Prevention (CDC) reports [3][4][5][6][7]. Elevated BLLs have become the first noninfection condition to be notifiable at the national level [7].…”