Introduction: Maternal behavior depends on a multitude of factors, including environmental ones, such as Endocrine Disrupting Chemicals (EDCs), which are increasingly attracting attention. Bisphenol A (BPA), an EDC present in plastic, is known to exert negative effects on maternal behavior. Bisphenol S (BPS), a BPA substitute, seems to share some endocrine disrupting properties. In this study, we focused on the analysis of the effects of low-dose (i.e., 4 µg/kg body weight/day, EFSA TDI for BPA) BPA or BPS exposure throughout pregnancy and lactation in mice. Methods: We administered adult C57BL/6 J females orally BPA, BPS, or vehicle from mating to offspring weaning. We assessed the number of pups at birth, the sex ratio, and the percentage of dead pups in each litter, and during the first postnatal week, we observed spontaneous maternal behavior. At the weaning of the pups, we sacrificed the dams and analyzed the oxytocin system, known to be involved in the control of maternal care, in the hypothalamic magnocellular nuclei. Results: At birth, pups from BPA-treated dams tended to have a lower male-to-female ratio compared to controls, while the opposite was observed among BPS-treated dams’ litters. During the first postnatal week, offspring mortality impacted differentially in the BPA and BPS litters, with more female dead pups among the BPA litters, while more male dead pups in the BPS litters, sharpening the difference in the sex ratio. BPA- and BPS-treated dams spent significantly less time in pup-related behaviors than controls. Oxytocin immunoreactivity in the paraventricular and supraoptic nuclei was increased only in the BPA-treated dams. Discussion/Conclusions: Alterations in maternal care, along with the treatment itself, may affect, later in life, the offspring’s physiology and behavior. Exposure to BPs during sensitive developmental periods represents a risk for both dams and offspring, even at low environmentally relevant doses, through the functional alteration of neural circuits controlling fundamental behaviors for pup survival, such as maternal behaviors.

1.
Gore
AC
,
Chappell
VA
,
Fenton
SE
,
Flaws
JA
,
Nadal
A
,
Prins
GS
,
.
EDC-2: the endocrine society’s second scientific statement on endocrine-disrupting chemicals
.
Endocr Rev
.
2015
;
36
(
6
):
E1
150
.
2.
Street
ME
,
Angelini
S
,
Bernasconi
S
,
Burgio
E
,
Cassio
A
,
Catellani
C
,
.
Current knowledge on endocrine disrupting chemicals (EDCs) from animal biology to humans, from pregnancy to adulthood: highlights from a national italian meeting
.
Int J Mol Sci
.
2018
;
19
(
6
):
E1647
.
3.
Ribeiro
E
,
Ladeira
C
,
Viegas
S
.
EDCs mixtures: a stealthy hazard for human health
.
Toxics
.
2017
;
5
(
1
):
E5
17
.
4.
Bakoyiannis
I
,
Kitraki
E
,
Stamatakis
A
.
Endocrine-disrupting chemicals and behaviour: a high risk to take
.
Best Pr Res Clin Endocrinol Metab
.
2021
;
35
(
5
):
101517
.
5.
Itoh
K
,
Yaoi
T
,
Fushiki
S
.
Bisphenol A, an endocrine-disrupting chemical, and brain development
.
Neuropathology
.
2012
;
32
(
4
):
447
57
.
6.
Gioiosa
L
,
Parmigiani
S
,
Vom Saal
FS
,
Palanza
P
.
The effects of bisphenol A on emotional behavior depend upon the timing of exposure, age and gender in mice
.
Horm Behav
.
2013
;
63
(
4
):
598
605
.
7.
Wolstenholme
JT
,
Rissman
EF
,
Connelly
JJ
.
The role of Bisphenol A in shaping the brain, epigenome and behavior
.
Horm Behav
.
2011
;
59
(
3
):
296
305
.
8.
Lehmler
HJ
,
Liu
B
,
Gadogbe
M
,
Bao
W
.
Exposure to bisphenol A, bisphenol F, and bisphenol S in U.S. Adults and children: the national health and nutrition examination survey 2013–2014
.
ACS Omega
.
2018
;
3
(
6
):
6523
32
.
9.
Catenza
CJ
,
Farooq
A
,
Shubear
NS
,
Donkor
KK
.
A targeted review on fate, occurrence, risk and health implications of bisphenol analogues
.
Chemosphere
.
2021
;
268
:
129273
.
10.
Rosenfeld
CS
.
Bisphenol A and phthalate endocrine disruption of parental and social behaviors
.
Front Neurosci
.
2015
;
9
:
57
.
11.
Keller
M
,
Vandenberg
LN
,
Charlier
TD
.
The parental brain and behavior: a target for endocrine disruption
.
Front Neuroendocr
.
2019
;
54
:
100765
.
12.
Mhaouty-Kodja
S
,
Belzunces
LP
,
Canivenc
MC
,
Schroeder
H
,
Chevrier
C
,
Pasquier
E
.
Impairment of learning and memory performances induced by BPA: evidences from the literature of a MoA mediated through an ED
.
Mol Cell Endocrinol
.
2018
;
475
:
54
73
.
13.
Bi
N
,
Ding
J
,
Zou
R
,
Gu
X
,
Liu
ZH
,
Wang
HL
.
Developmental exposure of bisphenol A induces spatial memory deficits by weakening the excitatory neural circuits of CA3-CA1 and EC-CA1 in mice
.
Toxicol Appl Pharmacol
.
2021 Sep
;
426
:
115641
.
14.
Kuruto-Niwa
R
,
Nozawa
R
,
Miyakoshi
T
,
Shiozawa
T
,
Terao
Y
.
Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system
.
Env Toxicol Pharmacol
.
2005
;
19
(
1
):
121
30
.
15.
Thoene
M
,
Dzika
E
,
Gonkowski
S
,
Wojtkiewicz
J
.
Bisphenol S in food causes hormonal and obesogenic effects comparable to or worse than bisphenol A: a literature review
.
Nutrients
.
2020
;
12
(
2
):
E532
.
16.
Liao
C
,
Liu
F
,
Alomirah
H
,
Loi
VD
,
Mohd
MA
,
Moon
HB
,
.
Bisphenol S in urine from the United States and seven Asian countries: occurrence and human exposures
.
Environ Sci Technol
.
2012
;
46
(
12
):
6860
6
.
17.
Bousoumah
R
,
Leso
V
,
Iavicoli
I
,
Huuskonen
P
,
Viegas
S
,
Porras
SP
,
.
Biomonitoring of occupational exposure to bisphenol A, bisphenol S and bisphenol F: a systematic review
.
Sci Total Env
.
2021
:
783
:
146905
.
18.
Eladak
S
,
Grisin
T
,
Moison
D
,
Guerquin
MJ
,
N’Tumba-Byn
T
,
Pozzi-Gaudin
S
,
.
A new chapter in the bisphenol a story: bisphenol S and bisphenol F are not safe alternatives to this compound
.
Fertil Steril
;
103
:
2015
:
11
21
.
19.
Chen
D
,
Kannan
K
,
Tan
H
,
Zheng
Z
,
Feng
YL
,
Wu
Y
,
.
Bisphenol analogues other than BPA: environmental occurrence, human exposure, and toxicity: a review
.
Environ Sci Technol
.
2016
;
50
(
11
):
5438
53
.
20.
Li
Y
,
Perera
L
,
Coons
LA
,
Burns
KA
,
Tyler Ramsey
J
,
Pelch
KE
,
.
Differential in vitro biological action, coregulator interactions, and molecular dynamic analysis of Bisphenol A (BPA), BPAF, and BPS ligand-Erα complexes.
.
Env Heal Perspect
.
2018
;
126
(
1
):
17012
.
21.
Beausoleil
C
,
Le Magueresse-Battistoni
B
,
Viguié
C
,
Babajko
S
,
Canivenc-Lavier
MC
,
Chevalier
N
,
.
Regulatory and academic studies to derive reference values for human health: The case of bisphenol S
.
Environ Res
.
2022 Mar
;
204
(
Pt C
):
112233
.
22.
Naderi
M
,
Kwong
RWM
.
A comprehensive review of the neurobehavioral effects of bisphenol S and the mechanisms of action: new insights from in vitro and in vivo models
.
Env Int
.
2020
;
145
:
106078
.
23.
Kohl
J
,
Autry
AE
,
Dulac
C
.
The neurobiology of parenting: a neural circuit perspective
.
Bioessays
.
2017
;
39
(
1
):
1
11
.
24.
Bealer
SL
,
Armstrong
WE
,
Crowley
WR
.
Oxytocin release in magnocellular nuclei: neurochemical mediators and functional significance during gestation
.
Am J Physiol Regul Integr Comp Physiol
.
2010
;
299
(
2
):
R452
8
.
25.
Panaro
MA
,
Benameur
T
,
Porro
C
.
Hypothalamic neuropeptide brain protection: focus on oxytocin
.
J Clin Med
.
2020
;
9
(
5
):
E1534
.
26.
Althammer
F
,
Eliava
M
,
Grinevich
V
.
Central and peripheral release of oxytocin: relevance of neuroendocrine and neurotransmitter actions for physiology and behavior
.
Handb Clin Neurol
.
2021
;
180
:
25
44
.
27.
Sanson
A
,
Bosch
OJ
.
Dysfunctions of brain oxytocin signaling: Implications for poor mothering
.
Neuropharmacology
.
2022 Apr
;
211
:
109049
.
28.
Caldwell
HK
,
Aulino
EA
,
Freeman
AR
,
Miller
TV
,
Witchey
SK
.
Oxytocin and behavior: lessons from knockout mice
.
Dev Neurobiol
.
2017
;
77
(
2
):
190
201
.
29.
Yoshihara
C
,
Numan
M
,
Kuroda
KO
.
Oxytocin and parental behaviors
.
Curr Top Behav Neurosci
.
2017
;
35
:
119
53
.
30.
Patisaul
HB
.
Achieving CLARITY on bisphenol A, brain and behaviour
.
J Neuroendocr
.
2020
;
32
(
1
):
e12730
.
31.
Boudalia
S
,
Berges
R
,
Chabanet
C
,
Folia
M
,
Decocq
L
,
Pasquis
B
,
.
A multi-generational study on low-dose BPA exposure in Wistar rats: effects on maternal behavior, flavor intake and development
.
Neurotoxicol Teratol
.
2014
;
41
:
16
26
.
32.
Della Seta
D
,
Minder
I
,
Dessì-Fulgheri
F
,
Farabollini
F
.
Bisphenol-A exposure during pregnancy and lactation affects maternal behavior in rats
.
Brain Res Bull
.
2005 Apr
;
65
(
3
):
255
60
.
33.
Kundakovic
M
,
Gudsnuk
K
,
Franks
B
,
Madrid
J
,
Miller
RL
,
Perera
FP
,
.
Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure
.
Proc Natl Acad Sci U S A
.
2013
;
110
(
24
):
9956
61
.
34.
Nakagami
A
,
Negishi
T
,
Kawasaki
K
,
Imai
N
,
Nishida
Y
,
Ihara
T
,
.
Alterations in male infant behaviors towards its mother by prenatal exposure to bisphenol A in cynomolgus monkeys (Macaca fascicularis) during early suckling period
.
Psychoneuroendocrinology
.
2009 Sep
;
34
(
8
):
1189
97
.
35.
Palanza
PL
,
Howdeshell
KL
,
Parmigiani
S
,
vom Saal
FS
.
Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice
.
Environ Health Perspect
.
2002
;
110
(
Suppl 3
):
415
22
.
36.
Catanese
MC
,
Vandenberg
LN
.
Bisphenol S (BPS) alters maternal behavior and brain in mice exposed during pregnancy/lactation and their daughters
.
Endocrinology
.
2016
;
158
(
3
):
516
30
.
37.
LaPlante
CD
,
Catanese
MC
,
Bansal
R
,
Vandenberg
LN
.
Bisphenol S alters the lactating mammary gland and nursing behaviors in mice exposed during pregnancy and lactation
.
Endocrinology
.
2017
;
158
(
10
):
3448
61
.
38.
Alonso-Magdalena
P
,
Vieira
E
,
Soriano
S
,
Menes
L
,
Burks
D
,
Quesada
I
,
.
Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring
.
Env Heal Perspect
.
2010
;
118
(
9
):
1243
50
.
39.
Alonso-Magdalena
P
,
Garcia-Arevalo
M
,
Quesada
I
,
Nadal
A
.
Bisphenol-A treatment during pregnancy in mice: a new window of susceptibility for the development of diabetes in mothers later in life
.
Endocrinology
.
2015
;
156
(
5
):
1659
70
.
40.
European Food Safety Authority Panel on Food Contact Materials Enzymes Flavourings and Processing Aids
.
Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs
.
EFSA J
.
2015
;
13
(
1
):
3978
.
41.
Hasegawa
A
,
Mochida
K
,
Ogonuki
N
,
Hirose
M
,
Tomishima
T
,
Inoue
K
,
.
Efficient and scheduled production of pseudopregnant female mice for embryo transfer by estrous cycle synchronization
.
J Reprod Dev
.
2017
;
63
(
6
):
539
45
.
42.
Kilkenny
C
,
Browne
WJ
,
Cuthill
IC
,
Emerson
M
,
Altman
DG
.
Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research
.
PloS Biol
.
2010
;
8
(
6
):
e1000412
.
43.
Bo
E
,
Farinetti
A
,
Marraudino
M
,
Sterchele
D
,
Eva
C
,
Gotti
S
,
.
Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice
.
Andrology
.
2016
;
4
(
4
):
723
34
.
44.
Palanza
P
,
Morellini
F
,
Parmigiani
S
,
vom Saal
FS
.
Ethological methods to study the effects of maternal exposure to estrogenic endocrine disrupters: a study with methoxychlor
.
Neurotoxicol Teratol
.
2002
;
24
(
1
):
55
69
.
45.
Bertocchi
I
,
Oberto
A
,
Longo
A
,
Mele
P
,
Sabetta
M
,
Bartolomucci
A
,
.
Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care
.
Proc Natl Acad Sci U S A
.
2011
;
108
(
48
):
19395
400
.
46.
Grech
V
.
The sex ratio at birth (2)
.
Early Hum Dev
.
2020
;
141
:
104866
.
47.
Bonaldo
B
,
Casile
A
,
Bettarelli
M
,
Gotti
S
,
Panzica
G
,
Marraudino
M
.
Effects of chronic exposure to bisphenol A in adult female mice on social behavior, vasopressin system, and estrogen membrane receptor (GPER1)
.
Eur J Histochem
.
2021
;
65
(
s1
):
3272
.
48.
Paxinos
G
,
Franklin
KBJ
,
Franklin
KBJ
.
The mouse brain in stereotaxic coordinates
. 2(nd) ed.
San Diego
:
Academic Press
;
2001
.
49.
Watson
RE
, Jr.
,
Wiegand
SJ
,
Clough
RW
,
Hoffman
GE
.
Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology
.
Peptides
.
1986
;
7
(
1
):
155
9
.
50.
Villanueva
C
,
Jacquier
S
,
de Roux
N
.
DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons
.
PloS One
.
2012
;
7
(
4
):
e36134
.
51.
Sawyer
HR
,
Moeller
CL
,
Kozlowski
GP
.
Immunocytochemical localization of neurophysin and oxytocin in ovine corpora lutea
.
Biol Reprod
.
1986
;
34
(
3
):
543
8
.
52.
Marraudino
M
,
Ponti
G
,
Moussu
C
,
Farinetti
A
,
Macchi
E
,
Accornero
P
,
.
Early postnatal genistein administration affects mice metabolism and reproduction in a sexually dimorphic way
.
Metabolites
.
2021
;
11
(
7
):
449
.
53.
Jacobson
MH
,
Ghassabian
A
,
Gore
AC
,
Trasande
L
.
Exposure to environmental chemicals and perinatal psychopathology
.
Biochem Pharmacol
.
2022 Jan
;
195
:
114835
.
54.
López-Rodríguez
D
,
Aylwin
CF
,
Delli
V
,
Sevrin
E
,
Campanile
M
,
Martin
M
,
.
Multi- and transgenerational outcomes of an exposure to a mixture of Endocrine-Disrupting Chemicals (EDCs) on puberty and maternal behavior in the female rat
.
Environ Health Perspect
.
2021 Aug
;
129
(
8
):
87003
.
55.
Witchey
SK
,
Fuchs
J
,
Patisaul
HB
.
Perinatal bisphenol A (BPA) exposure alters brain oxytocin receptor (OTR) expression in a sex- and region- specific manner: a CLARITY-BPA consortium follow-up study
.
Neurotoxicology
.
2019
;
74
:
139
48
.
56.
Acconcia
F
,
Pallottini
V
,
Marino
M
.
Molecular mechanisms of action of BPA
.
Dose Response
.
2016
;
13
(
4
):
155932581561058
.
57.
Iwamoto
M
,
Masuya
T
,
Hosose
M
,
Tagawa
K
,
Ishibashi
T
,
Suyama
K
,
.
Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β
.
J Biol Chem
.
2021 Nov
;
297
(
5
):
101173
.
58.
Hiroi
H
,
Tsutsumi
O
,
Momoeda
M
,
Takai
Y
,
Osuga
Y
,
Taketani
Y
.
Differential interactions of bisphenol A and 17beta-estradiol with estrogen receptor alpha (Eralpha) and Erbeta
.
Endocr J
.
2000
;
46
(
6
):
773
8
.
59.
Mitra
SW
,
Hoskin
E
,
Yudkovitz
J
,
Pear
L
,
Wilkinson
HA
,
Hayashi
S
,
.
Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha.
.
Endocrinology
.
2003
;
144
(
5
):
2055
67
.
60.
Nourian
A
,
Soleimanzadeh
A
,
Shalizar Jalali
A
,
Najafi
G
.
Bisphenol-A analogue (bisphenol-S) exposure alters female reproductive tract and apoptosis/oxidative gene expression in blastocyst-derived cells
.
Iran J Basic Med Sci
.
2020
;
23
(
5
):
576
85
.
61.
Grassi
D
,
Lagunas
N
,
Pinos
H
,
Panzica
G
,
Garcia-Segura
LM
,
Collado
P
.
NADPH-Diaphorase colocalizes with GPER and is modulated by the GPER agonist G1 in the supraoptic and paraventricular nuclei of ovariectomized female rats
.
Neuroendocrinology
.
2017
;
104
(
1
):
94
104
.
62.
Marraudino
M
,
Carrillo
B
,
Bonaldo
B
,
Llorente
R
,
Campioli
E
,
Garate
I
,
.
G protein-coupled estrogen receptor immunoreactivity in the rat hypothalamus is widely distributed in neurons, astrocytes, and oligodendrocytes, fluctuates during the estrous cycle, and is sexually dimorphic.
.
Neuroendocrinology
.
2021
;
111
(
7
):
660
77
.
63.
Carcea
I
,
Caraballo
NL
,
Marlin
BJ
,
Ooyama
R
,
Riceberg
JS
,
Mendoza Navarro
JM
,
.
Oxytocin neurons enable social transmission of maternal behaviour
.
Nature
.
2021 Aug
;
596
(
7873
):
553
7
.
64.
Jiang
QB
,
Wakerley
JB
.
Analysis of bursting responses of oxytocin neurones in the rat in late pregnancy, lactation and after weaning
.
J Physiol
.
1995 Jul
;
486
(
Pt 1
):
237
48
.
65.
Shi
M
,
Sekulovski
N
,
MacLean
JA
,
Whorton
A
,
Hayashi
K
.
Prenatal exposure to bisphenol a analogues on female reproductive functions in mice
.
Toxicol Sci
.
2019
;
168
(
2
):
561
71
.
66.
Shi
M
,
Whorton
AE
,
Sekulovski
N
,
MacLean
JA
,
Hayashi
K
.
Prenatal exposure to bisphenol A, E, and S induces transgenerational effects on female reproductive functions in mice
.
Toxicol Sci
.
2019
;
170
(
2
):
320
9
.
67.
Kobayashi
K
,
Ohtani
K
,
Kubota
H
,
Miyagawa
M
.
Dietary exposure to low doses of bisphenol A: effects on reproduction and development in two generations of C57BL/6J mice
.
Congenit Anom
.
2010
;
50
(
3
):
159
70
.
68.
Rubin
BS
.
Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects
.
J Steroid Biochem Mol Biol
.
2011
;
127
(
1–2
):
27
34
.
69.
Vom Saal
FS
.
TRIENNIAL REPRODUCTION SYMPOSIUM: Environmental programming of reproduction during fetal life: Effects of intrauterine position and the endocrine disrupting chemical bisphenol A
.
J Anim Sci
.
2016
;
94
(
7
):
2722
36
.
70.
Chianese
R
,
Troisi
J
,
Richards
S
,
Scafuro
M
,
Fasano
S
,
Guida
M
,
.
Bisphenol a in reproduction: epigenetic effects
.
Curr Med Chem
.
2017
;
25
(
6
):
748
70
.
71.
Pergialiotis
V
,
Kotrogianni
P
,
Christopoulos-Timogiannakis
E
,
Koutaki
D
,
Daskalakis
G
,
Papantoniou
N
.
Bisphenol A and adverse pregnancy outcomes: a systematic review of the literature
.
J Matern Fetal Neonatal Med
.
2018
;
31
(
24
):
3320
7
.
72.
Filardi
T
,
Panimolle
F
,
Lenzi
A
,
Morano
S
.
Bisphenol a and phthalates in diet: an emerging link with pregnancy complications
.
Nutrients
.
2020
;
12
(
2
):
E525
.
You do not currently have access to this content.