Estrogen Formation and Inactivation Following TBI: What we Know and Where we Could go

Abstract

Traumatic brain injury (TBI) is responsible for various neuronal and cognitive deficits as well as psychosocial dysfunction. Characterized by damage inducing neuroinflammation, this response can cause an acute secondary injury that leads to widespread neurodegeneration and loss of neurological function. Estrogens decrease injury induced neuroinflammation and increase cell survival and neuroprotection and thus are a potential target for use following TBI. While much is known about the role of estrogens as a neuroprotective agent following TBI, less is known regarding their formation and inactivation following damage to the brain. Specifically, very little is known surrounding the majority of enzymes responsible for the production of estrogens. These estrogen metabolizing enzymes (EME) include aromatase, steroid sulfatase (STS), estrogen sulfotransferase (EST/SULT1E1), and some forms of 17β-hydroxysteroid dehydrogenase (HSD17B) and are involved in both the initial conversion and interconversion of estrogens from precursors. This article will review and offer new prospective and ideas on the expression of EMEs following TBI.

Keywords: HSD17B; TBI; androgen; aromatase; estrogen; sulfatase.

Figure 1

Schematic representation of the enzymatic conversion and synthesis of biologically active estrogens. Estrogens are produced from C19 steroid precursors through several enzymatic conversions. DHEA, dehydroepiandrosterone. DHEA-S, dehydroepiandrosterone-sulfate; Aromatase/CYP19A1, estrogen synthase; HSD3B1, hydroxysteroid 3 beta-1; HSD3B2, hydroxysteroid 3 beta-2; HSD17B1, hydroxysteroid 17-beta dehydrogenase; HSD17B2, hydroxysteroid 17-beta dehydrogenase 2; STS, steroid sulfatase; SULT2A1, Sulfotransferase Family 2A Member 1; SULT2B1, Sulfotransferase Family 2B Member 1; SULT1E1, estrogen sulfotransferase; AKR1C3, Aldo-Keto Reductase Family 1 Member C3; CYP3A4, Cytochrome P450 3A4.

Figure 2

Levels of EMEs mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT value and fold change) in both male and female zebra finches 24 h post-surgery. Adult male and female zebra finches were subjected to an unilateral penetrating injury directed toward the entopallium and collected 24 h later. Finches were sacrificed and total RNA was extracted from microdissections immediately adjacent to the cortical needle and the corresponding location on uninjured hemisphere. Expression of STS (A), SULT1E1 (C), HSD17B1 (E), and HSD17B2 (G) relative to GAPDH was measured using quantitative PCR using primers specific for the ZF mRNA sequence. Mean ΔCT values were compared with a two-way ANOVA. Fold change in gene expression was also calculated STS (B), SULT1E1 (D), HSD17B1 (F), and HSD17B2 (H). Neither expression of STS, SULT1E1, or HSD17B1 were significantly changed following injury. However, HSD17B2 was significantly downregulated following injury. *denotes a significant difference at P < 0.05. All protocols were approved by the Vassar College Institutional Animal Care and Use Committee following National Institutes of Health Guidelines.