10.5061/DRYAD.5MKKWH72T
Brooks, David C.
Northwestern University
Coon V, John S.
Northwestern University
Ercan, Cihangir M.
Northwestern University
Xu, Xia
Frederick National Laboratory for Cancer Research
Dong, Hongxin
Northwestern University
Levine, Jon E.
University of Wisconsin System
Bulun, Serdar E.
Northwestern University
Zhao, Hong
0000-0003-4616-3123
Northwestern University
Brain aromatase and the regulation of sexual activity in male mice
Dryad
dataset
2020
Aromatase
Estrogen
Testosterone
Sexual behavior
2020-09-18T00:00:00Z
2020-09-18T00:00:00Z
en
https://doi.org/10.1210/endocr/bqaa137
41276264 bytes
5
CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
The biologically active estrogen, estradiol, has important roles in adult
brain physiology and sexual behavior. A single gene, Cyp19a1, encodes
aromatase, the enzyme that catalyzes the conversion of testosterone to
estradiol in the testis and brain of male mice. Estradiol formation was
shown to regulate sexual activity in various species, but the relative
contributions to sexual behavior of estrogen arising in the brain versus
gonads remained unclear. To determine the role of brain aromatase in
regulating male sexual activity, we generated a brain-specific aromatase
knockout (bArKO) mouse. A newly generated whole-body total aromatase
knockout mouse of the same genetic background served as a positive
control. Here we demonstrate that local aromatase expression and estrogen
production in the brain is partially required for male sexual behavior and
sex hormone homeostasis. Male bArKO mice exhibited decreased sexual
activity in the presence of strikingly elevated circulating testosterone.
In castrated adult bArKO mice, administration of testosterone only
partially restored sexual behavior; full sexual behavior, however, was
achieved only when both estradiol and testosterone were administered
together. Thus, aromatase in the brain is, in part, necessary for
testosterone-dependent male sexual activity. We also found that brain
aromatase is required for negative feedback regulation of circulating
testosterone of testicular origin. Our findings suggest testosterone
activates male sexual behavior in part via conversion to estradiol in the
brain. These studies provide foundational evidence that sexual behavior
may be modified through inhibition or enhancement of brain aromatase
enzyme activity and/or utilization of selective estrogen receptor
modulators.
This data collection details the following supplemental figures and movies
associated with the manuscript, determining the role of aromatase and
estrogen in male sexual behavior. Supplemental Figure 1. Fertility of
bArKO and tArKO mice. Average litter size of bArKO (A) or tArKO male mice
(B). The average number of pups per litter was calculated when bArKO or
control (heterozygous) males were mated with age-matched WT females or
tArKO or control (heterozygous) males were mated with age-matched WT
females for 4 months. 2-tailed Student’s t test, *P < 0.05, n=5 per
group. Supplemental Figure 2. Body weight of bArKO and tArKO mice. Body
weight was assessed weekly from 3 to 48 weeks of age in (A) bArKO and (B)
tArKO mice. Age-matched heterozygous male mice were used as controls.
2-tailed Student’s t test, *P < 0.05, n=7-8 for controls, n=8 for
bArKO mice, n=7 for tArKO mice. Supplemental Figure 3. Tissue testosterone
(T) and androstenedione (A4) levels in bArKO mice. Brain levels of T (A)
and A4 (B) and testis levels of T (C) and A4 (D) were measured by LC-MS2
assay. 2-tailed Student’s t test, n=9-12 for heterozygous controls, n=6
for bArKO mice. Mouse tissues were collected from 8- to 26-week-old mice
(A-D). Supplemental Figure 4. Tissue androgen levels in tArKO mice. Brain
levels of testosterone (T) (A) and androstenedione (A4) (B) and testis
levels of T (C) and A4 (D) were measured by LC-MS2 assay. 2-tailed
Student’s t test or one-way ANOVA with Tukey’s multiple comparison test,
*P < 0.05, **P < 0.01, ****P < 0.0001, n=21 for WT,
n=25 for heterozygous controls (Het), and n=16 for tArKO mice (A and B);
n=8-9 for WT, n=6-7 for heterozygous controls (Het), and n=6 for tArKO
mice (C and D). Mouse tissues were collected from 8- to 26-week-old mice
(A-D). Movie S1. Representative sexual behavior movie for a male bArKO
mouse (black). The white mouse is an unfamiliar, hormonally primed, and
sexually experienced female mouse. Movie S2. Representative sexual
behavior movie for a male heterozygous mouse (Control, black) served as a
control for bArKO mice. The white mouse is an unfamiliar, hormonally
primed, and sexually experienced female mouse. Movie S3. Representative
sexual behavior movie for a male tArKO mouse (black). The white mouse is
an unfamiliar, hormonally primed, and sexually experienced female mouse.
Movie S4. Representative sexual behavior movie for a male heterozygous
mouse (Het, black) served as a control for tArKO mice. The white mouse is
an unfamiliar, hormonally primed, and sexually experienced female mouse.
Movie S5. Representative sexual behavior movie for a male WT mouse (black)
served as a control for tArKO mice. The white mouse is an unfamiliar,
hormonally primed, and sexually experienced female mouse.