Introduction: Being born either large for gestational age (LGA) or small for gestational age has been associated with an increased risk of developing metabolic syndrome in adulthood. However, the mechanism underlying this early programming remained unclear. Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor with a high expression in the human placenta, particularly ERRγ1. ERRγ has been proposed to play a central role in controlling genes involved in energy metabolism. In the placenta, ERRγ1 acts as an oxygen-responsive transcription factor, regulating aromatase expression during trophoblast differentiation. Aromatase is an enzyme that catalyzes the synthesis of estrogens from androgens and is located in the syncytiotrophoblast. An adequate estrogen-androgen balance is required for normal pregnancy progression. Our aim was to analyze ERRγ1 and aromatase mRNA in human placenta from term LGA newborns. We propose that ERRγ1 and CYP19A1 expressions in the human placenta of LGA newborns are impaired, which would modify the fetal programming of LGA newborns since an imbalance in the intrauterine estrogen-androgen ratio would occur. Methods: Total RNA was obtained from the placental tissues of LGA (GA: 39–41 weeks, n = 8) and adequate for gestational age (AGA; 39–40 weeks, n = 10) newborns. ERRγ1 and aromatase mRNA variants were analyzed by RT2-PCR. Primers for aromatase analysis were specific for total aromatase (TotalAro) binding in exons 2–3 and for active aromatase (ActAro) in exons 9–10. Aromatase protein was analyzed by Western blot. Results: ERRγ1 mRNA was significantly higher in LGA compared to AGA. TotalAro mRNA was significantly lower in LGA in comparison with AGA control. Similar results were observed with aromatase protein. In contrast, ActAro/TotalAro ratio was higher in LGA compared to the AGA control. Conclusions: High expression of ERRγ1 as well as ActAro/TotalAro ratio in LGA suggests that ERRγ1 is involved in ActAro variant expression and hence disrupted estrogen-androgen balance in the intrauterine environment. We propose that dysregulation of ERRγ1 in the placenta might modify the estrogen-androgen balance in the intrauterine environment in LGA newborns, possibly representing one of the key factors in the regulation of fetal programming.

Events during fetal development are associated with susceptibility to chronic disease in adulthood. Extreme birth weight, for newborns of small for gestational age or large for gestational age (LGA), has been associated with an increased risk of developing metabolic syndrome in adulthood. Even though some intrauterine events during fetal development have been described, there is still a long way for identifying all the factors that are involved in fetal programming. The placenta has an important role in intrauterine programming because it controls the intrauterine environment by supplying oxygen, nutrients, and specific hormones involved in fetal development. Estrogens and androgens in maternal and fetal circulations play an important role in determining a physiological placental phenotype. ERRγ1 expression in placental tissues is involved in aromatase activity regulation and hence in intrauterine estrogen-androgen balance. In this study, we propose that the dysregulation of ERRγ1 in placental tissue might modify the estrogen-androgen balance in the intrauterine environment, representing one of the key factors in the regulation of fetal programming in LGA newborns.

1.
Burton
GJ
,
Fowden
AL
,
Thornburg
KL
.
Placental origins of chronic disease
.
Physiol Rev
.
2016
;
96
(
4
):
1509
65
.
2.
Barker
DJ
.
The origins of the developmental origins theory
.
J Intern Med
.
2007
;
261
(
5
):
412
7
.
3.
Harder
T
,
Rodekamp
E
,
Schellong
K
,
Dudenhausen
JW
,
Plagemann
A
.
Birth weight and subsequent risk of type 2 diabetes: a meta-analysis
.
Am J Epidemiol
.
2007
;
165
(
8
):
849
57
.
4.
Dyer
JS
,
Rosenfeld
CR
,
Rice
J
,
Rice
M
,
Hardin
DS
.
Insulin resistance in Hispanic large-for-gestational-age neonates at birth
.
J Clin Endocrinol Metab
.
2007
;
92
(
10
):
3836
43
.
5.
Bizerea-Moga
TO
,
Pitulice
L
,
Pantea
CL
,
Olah
O
,
Marginean
O
,
Moga
TV
.
Extreme birth weight and metabolic syndrome in children
.
Nutrients
.
2022
;
14
(
1
):
204
.
6.
Huang
R
,
Dong
Y
,
Levy
E
,
Julien
P
,
Marc
I
,
He
H
, et al
.
Large-for-Gestational-Age, leptin, and adiponectin in infancy
.
J Clin Endocrinol Metab
.
2022
;
107
(
2
):
e688
97
.
7.
Ehrenberg
HM
,
Mercer
BM
,
Catalano
PM
.
The influence of obesity and diabetes on the prevalence of macrosomia
.
Am J Obstet Gynecol
.
2004
;
191
(
3
):
964
8
.
8.
Silverman
BL
,
Rizzo
TA
,
Cho
NH
,
Metzger
BE
.
Long-term effects of the intrauterine environment. The northwestern university diabetes in pregnancy center
.
Diabetes Care
.
1998
;
21
(
Suppl 2
):
B142
9
.
9.
Corbould
A
.
Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome
.
Diabetes Metab Res Rev
.
2008
;
24
(
7
):
520
32
.
10.
Padmanabhan
V
,
Cardoso
RC
,
Puttabyatappa
M
.
Developmental programming, a pathway to disease
.
Endocrinology
.
2016
;
157
(
4
):
1328
40
.
11.
Svensson
K
,
Just
AC
,
Fleisch
AF
,
Sanders
AP
,
Tamayo-Ortiz
M
,
Baccarelli
AA
, et al
.
Prenatal salivary sex hormone levels and birth-weight-for-gestational age
.
J Perinatol
.
2019
;
39
(
7
):
941
8
.
12.
Hartwig
IR
,
Pincus
MK
,
Diemert
A
,
Hecher
K
,
Arck
PC
.
Sex-specific effect of first-trimester maternal progesterone on birthweight
.
Hum Reprod
.
2013
;
28
(
1
):
77
86
.
13.
Mucci
LA
,
Lagiou
P
,
Tamimi
RM
,
Hsieh
CC
,
Adami
HO
,
Trichopoulos
D
.
Pregnancy estriol, estradiol, progesterone and prolactin in relation to birth weight and other birth size variables (United States)
.
Cancer Causes Control
.
2003
;
14
(
4
):
311
8
.
14.
Hakim
C
,
Padmanabhan
V
,
Vyas
AK
.
Gestational hyperandrogenism in developmental programming
.
Endocrinology
.
2017
;
158
(
2
):
199
212
.
15.
Pepe
G
,
Albrecht
E
.
Steroid endocrinology of pregnancy
.
Glob Libr Women’s Med
.
2009
.
16.
Means
GD
,
Mahendroo
MS
,
Corbin
CJ
,
Mathis
JM
,
Powell
FE
,
Mendelson
CR
, et al
.
Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis
.
J Biol Chem
.
1989
;
264
(
32
):
19385
91
.
17.
Bulun
SE
,
Sebastian
S
,
Takayama
K
,
Suzuki
T
,
Sasano
H
,
Shozu
M
.
The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters
.
J Steroid Biochem Mol Biol
.
2003
;
86
(
3–5
):
219
24
.
18.
Santen
RJ
,
Brodie
H
,
Simpson
ER
,
Siiteri
PK
,
Brodie
A
.
History of aromatase: saga of an important biological mediator and therapeutic target
.
Endocr Rev
.
2009
;
30
(
4
):
343
75
.
19.
Pepe
CM
,
Saraco
NI
,
Baquedano
MS
,
Guercio
G
,
Vaiani
E
,
Marino
R
, et al
.
The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of nonclassic aromatase deficiency and is also present in normal human steroidogenic tissues
.
Clin Endocrinol
.
2007
;
67
(
5
):
698
705
.
20.
Saraco
N
,
Nesi-Franca
S
,
Sainz
R
,
Marino
R
,
Marques-Pereira
R
,
La Pastina
J
, et al
.
An intron 9 CYP19 gene variant (IVS9+5G>A), present in an aromatase-deficient girl, affects normal splicing and is also present in normal human steroidogenic tissues
.
Horm Res Paediatr
.
2015
;
84
(
4
):
275
82
.
21.
Fournet-Dulguerov
N
,
MacLusky
NJ
,
Leranth
CZ
,
Todd
R
,
Mendelson
CR
,
Simpson
ER
, et al
.
Immunohistochemical localization of aromatase cytochrome P-450 and estradiol dehydrogenase in the syncytiotrophoblast of the human placenta
.
J Clin Endocrinol Metab
.
1987
;
65
(
4
):
757
64
.
22.
Krasic
J
,
Fucic
A
,
Sincic
N
,
Sindicic Dessardo
N
,
Starcevic
M
,
Guszak
V
, et al
.
Comparison of estradiol, testostosterone, and CYP19 methylation levels between full-term and preterm newborns
.
Horm Res Paediatr
.
2021
;
94
(
5–6
):
168
75
.
23.
Fujimoto
J
,
Nakagawa
Y
,
Toyoki
H
,
Sakaguchi
H
,
Sato
E
,
Tamaya
T
.
Estrogen-related receptor expression in placenta throughout gestation
.
J Steroid Biochem Mol Biol
.
2005
;
94
(
1–3
):
67
9
.
24.
Takeda
Y
,
Liu
X
,
Sumiyoshi
M
,
Matsushima
A
,
Shimohigashi
M
,
Shimohigashi
Y
.
Placenta expressing the greatest quantity of bisphenol A receptor ERR{gamma} among the human reproductive tissues: predominant expression of type-1 ERRgamma isoform
.
J Biochem
.
2009
;
146
(
1
):
113
22
.
25.
Kumar
P
,
Mendelson
CR
.
Estrogen-related receptor gamma (ERRgamma) mediates oxygen-dependent induction of aromatase (CYP19) gene expression during human trophoblast differentiation
.
Mol Endocrinol
.
2011
;
25
(
9
):
1513
26
.
26.
Poidatz
D
,
Dos Santos
E
,
Brulé
A
,
De Mazancourt
P
,
Dieudonné
MN
.
Estrogen-related receptor gamma modulates energy metabolism target genes in human trophoblast
.
Placenta
.
2012
;
33
(
9
):
688
95
.
27.
Poidatz
D
,
Dos Santos
E
,
Gronier
H
,
Vialard
F
,
Maury
B
,
De Mazancourt
P
, et al
.
Trophoblast syncytialisation necessitates mitochondrial function through estrogen-related receptor-γ activation
.
Mol Hum Reprod
.
2015
;
21
(
2
):
206
16
.
28.
Poidatz
D
,
Dos Santos
E
,
Duval
F
,
Moindjie
H
,
Serazin
V
,
Vialard
F
, et al
.
Involvement of estrogen-related receptor-γ and mitochondrial content in intrauterine growth restriction and preeclampsia
.
Fertil Steril
.
2015
;
104
(
2
):
483
90
.
29.
Guía para La evaluación del crecimiento físico
. Comité Nacional de Crecimiento y Desarrollo. SAP.
2013
. http://www.sap.org.ar/docs/publicaciones/libro_verde_sap_2013.pdf.
30.
Romani
C
,
Calza
S
,
Todeschini
P
,
Tassi
RA
,
Zanotti
L
,
Bandiera
E
, et al
.
Identification of optimal reference genes for gene expression normalization in a wide cohort of endometrioid endometrial carcinoma tissues
.
PLoS One
.
2014
;
9
(
12
):
e113781
.
31.
Radonić
A
,
Thulke
S
,
Mackay
IM
,
Landt
O
,
Siegert
W
,
Nitsche
A
.
Guideline to reference gene selection for quantitative real-time PCR
.
Biochem Biophys Res Commun
.
2004
;
313
(
4
):
856
62
.
32.
Lanoix
D
,
Lacasse
AA
,
St-Pierre
J
,
Taylor
SC
,
Ethier-Chiasson
M
,
Lafond
J
, et al
.
Quantitative PCR pitfalls: the case of the human placenta
.
Mol Biotechnol
.
2012
;
52
(
3
):
234
43
Erratum in: Mol Biotechnol. 2013 Jun;54(2):721-2.
33.
Di Rienzo
JA
,
Casanoves
F
,
Balzarini
MG
,
Gonzalez
L
,
Tablada
M
,
Robledo
CW
. InfoStat versión 2018. Grupo InfoStat, FCA, universidad nacional de Córdoba, Argentina. Available from: http://www.infostat.com.ar.
34.
Braun
T
,
Challis
JR
,
Newnham
JP
,
Sloboda
DM
.
Early-life glucocorticoid exposure: the hypothalamic-pituitary-adrenal axis, placental function, and long-term disease risk
.
Endocr Rev
.
2013
;
34
(
6
):
885
916
.
35.
Jansson
T
,
Powell
TL
.
Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches
.
Clin Sci
.
2007
;
113
(
1
):
1
13
.
36.
Ghnenis
AB
,
Odhiambo
JF
,
Smith
AM
,
Pankey
CL
,
Nathanielsz
PW
,
Ford
SP
.
A heretical view: rather than a solely placental protective function, placental 11β hydroxysteroid dehydrogenase 2 also provides substrate for fetal peripheral cortisol synthesis in obese pregnant ewes
.
J Dev Orig Health Dis
.
2021
;
12
(
1
):
94
100
.
37.
Boney
CM
,
Verma
A
,
Tucker
R
,
Vohr
BR
.
Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus
.
Pediatrics
.
2005
;
115
(
3
):
e290
6
.
38.
Bukovsky
A
,
Cekanova
M
,
Caudle
MR
,
Wimalasena
J
,
Foster
JS
,
Henley
DC
, et al
.
Expression and localization of estrogen receptor-alpha protein in normal and abnormal term placentae and stimulation of trophoblast differentiation by estradiol
.
Reprod Biol Endocrinol
.
2003
;
1
(
1
):
13
.
39.
Karahoda
R
,
Kallol
S
,
Groessl
M
,
Ontsouka
E
,
Anderle
P
,
Fluck
C
, et al
.
Revisiting steroidogenic pathways in the human placenta and primary human trophoblast cells
.
Int J Mol Sci
.
2021
;
22
(
4
):
1704
.
40.
Lagiou
P
,
Samoli
E
,
Hsieh
CC
,
Lagiou
A
,
Xu
B
,
Yu
GP
, et al
.
Maternal and cord blood hormones in relation to birth size
.
Eur J Epidemiol
.
2014
;
29
(
5
):
343
51
.
41.
Shen
Z
,
Tang
Y
,
Song
Y
,
Shen
W
,
Zou
C
.
Differences of DNA methylation patterns in the placenta of large for gestational age infant
.
Medicine
.
2020
;
99
(
39
):
e22389
.
42.
Gambino
YP
,
Maymó
JL
,
Pérez-Pérez
A
,
Dueñas
JL
,
Sánchez-Margalet
V
,
Calvo
JC
, et al
.
17Beta-estradiol enhances leptin expression in human placental cells through genomic and nongenomic actions
.
Biol Reprod
.
2010
;
83
(
1
):
42
51
.
43.
Schanton
M
,
Maymó
J
,
Camisay
MF
,
Pérez-Pérez
A
,
Casale
R
,
Sánchez-Margalet
V
, et al
.
Crosstalk between estradiol and NFκB signaling pathways on placental leptin expression
.
Reproduction
.
2020
;
160
(
4
):
591
602
.
44.
Dong
Y
,
Luo
ZC
,
Nuyt
AM
,
Audibert
F
,
Wei
SQ
,
Abenhaim
HA
, et al,
3D Cohort Study Group
.
Large-for-Gestational-Age may Be associated with lower fetal insulin sensitivity and β-cell function linked to leptin
.
J Clin Endocrinol Metab
.
2018
;
103
(
10
):
3837
44
.
45.
Lausten-Thomsen
U
,
Christiansen
M
,
Hedley
PL
,
Holm
JC
,
Schmiegelow
K
.
Adipokines in umbilical cord blood from children born large for gestational age
.
J Pediatr Endocrinol Metab
.
2016
;
29
(
1
):
33
7
.
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