Hormonal and Chemical Regulation of Paraoxonases in Mice

Abstract

In humans and rodents, paraoxonase (PON/Pon) 1 expression and activity in livers and serum are higher in females than in males, and some drugs increase paraoxonase's expression. However, the underlining mechanisms of gender-divergent expression and chemical regulation of Pon1 remain largely unknown. The present study determined the regulatory mechanisms contributing to gender-divergent and chemically altered Pon expression in mouse livers. Pon1 mRNA was much more abundant in the livers of mice than other tissues, with higher levels in female livers than male livers at mRNA and protein levels. Pon2 mRNA was ubiquitously expressed in mouse tissues, but minimally in mouse liver. Pon3 mRNA was most abundant in mouse lung and liver and less abundant in other tissues. Pon1 mRNA was lowest in fetal liver, markedly increased at parturition, and remained relatively constant thereafter. Pon2 and Pon3 mRNA are highly expressed in fetal liver and decreased after birth. Male-pattern growth hormone (GH) administration in hypophysectomized and lit/lit mice decreased Pon1 expression. Sex hormones and female-pattern GH administration had no effect on Pon1 expression, indicating the importance of male-pattern GH in regulating Pon1. Aryl hydrocarbon receptor, pregnane X receptor, and NF-E2-related factor activators had no effect on Pon1 mRNA. A constitutive androstane receptor (CAR) activator decreased Pon1 expression in wild-type but not CAR-null mice. In conclusion, Pon1 mRNA was most abundant in adult mouse livers, whereas Pon2 and Pon3 mRNAs were most abundant in fetal mouse livers. Female-predominant Pon1 expression in mouse livers is caused by the inhibitory effects of male-pattern GH secretion, and CAR activation decreases Pon1 expression.

RNA Sequencing Quantification of Xenobiotic-Processing Genes in Various Sections of the Intestine in Comparison to the Liver of Male Mice

“…For Pons, the present study has shown that both Pon2 and 3 mRNAs are lower in the jejunum and ileum than in the large intestine, in contrast to the previous report of similar levels (Cheng and Klaassen, 2012). For Akrs, the mRNAs of Akr1a1/1a4, 1b3, 1c12, 1c13, 1c19, and 1e1 in certain tissue(s) in the present study are not fully consistent with a previous report (Pratt-Hyatt et al, 2013).…”

Developmental expression of paraoxonase 2

“…Unfortunately, non-human primate liver samples were not available for analysis, and the persistence of expression patterns between species for PON2 in the liver is unclear. Previous studies had examined the developmental expression of PON1 mRNA in liver and of paraoxonase activity in plasma of mice, and found PON1 levels to increase with age [35–37], in agreement with the present findings. PON3 temporal expression has received less attention, with limited studies showing a decrease or an increase with age [37–39].…”

Impact of the X Chromosome and sex on regulatory variation

“…If tested separately in each sex, this gene-SNP pair is an eQTL in males (P-value = 5.5 × 10 −3 ) but not females (P-value = 5.0 × 10 −1 ). Interestingly, PON2 does not exhibit sex-specific gene expression (P-value = 6.3 × 10 −1 , FDR 89.2%) but has been associated with sex-specific effects in oxidative stress responses (Cheng and Klaassen 2012;Giordano et al 2013;Polonikov et al 2014). …”