Abstract
The mu-opioid receptor is encoded by the Oprm1 gene and contributes to mother–infant behaviors. Rodent dams lick male pups more than female pups in the anogenital region. This behavior is linked to stress responsivity in the offspring that may be mediated by epigenetic changes. We hypothesized that maternal behavior may affect DNA methylation levels of the Oprm1 gene and show sex differences. To further explore sex differences in mother–pup behaviors and DNA methylation levels, we altered the litter gender composition (LGC) of rats. Litters were culled to eight all male, all female, or four male/four female pups on postnatal (PN) day 1. On PN4, 7, and 10, a dam was placed in a test cage with a pup for a 10-min period. Latency to pup contact was determined as were times spent licking the anogenital and other body regions of the pup. Frequencies of other behaviors were tabulated. On PN35, samples from various brain regions were obtained. DNA methylation at specific CpG sites in the Oprm1 promoter region were measured by direct sequencing of bisulfite-treated DNA. LGC and sex interacted with day for latency to pup contact. Latencies were longest on PN4 for single-sex males and on PN10 for single-sex females. Dams licked male pups more than female pups in both the anogenital and other body areas. Sex differences were seen in other behaviors. LGC altered DNA methylation at specific CpG's of Oprm1 in hippocampus with higher levels in single-sex rats. In nucleus accumbens, single-sex males showed hypermethylation levels, a trend seen in caudate–putamen. Results confirm and extend sex differences in maternal care with modest LGC effects. That both LGC and sex have enduring effects on DNA methylation of the Oprm1 gene in brain regions associated with addiction, stress regulation, motivation, and cognition may suggest one factor that contributes to gender differences in these behaviors.
Highlights
Males and females differ in incidences of several behavioral disorders
The dam’s behavior of grooming herself shows a trend toward significance for the Sex × Day interaction, F(2,76) = 2.38; P < 0.10 and this likely reflects that her grooming tends to decrease over days with male pups but tends to increase over days with female pups
These experiments provide important new data on epigenetic alterations linked to the subtle early life manipulation of modifying litter gender composition (LGC) as well as to sex differences both of which affected maternal behavior
Summary
Males and females differ in incidences of several behavioral disorders. Autism, antisocial personality and addictive disorders are more common in men, whereas depressive and anxiety disorders are more common in women (Fombonne, 2003; Grant et al, 2009; Vigod and Stewart, 2009). Alcoholism and drug addiction are more common in men, women progress more quickly from initial use to abuse and dependence (Greenfield et al, 2010). Women are just as likely as men to use or abuse prescription opiate drugs (McCabe et al, 2005). Stress exposure, that can precipitate behavioral disorders (Sinha, 2001; Caspi et al, 2003), has greater effects in women than men (Kudielka and Kirschbaum, 2005). A cascade of events occurs in which corticotrophinreleasing factor release from the paraventricular nucleus of the hypothalamus stimulates the pituitary to cleave proopiomelanocortin into adrenocorticotropic hormone (ACTH) and the endogenous opioid, beta-endorphin as well as other peptides. Beta-endorphins interact with opioid receptors, mu-type receptors, both centrally and in the periphery
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