Aquaculture and Fisheries 7 (2022) 525–539

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Aquaculture and Fisheries

journal homepage: www.keaipublishing.com/en/journals/aquaculture-and-fisheries

Review article

Sexual plasticity in bony fishes: Analyzing morphological to molecular

changes of sex reversal
Swathi Tenugu, Balasubramanian Senthilkumaran *
Department of Animal Biology, School of Life Sciences, University of Hyderabad, P.O. Central University, Hyderabad, 500046, India

A R T I C L E I N F O A B S T R A C T

Keywords: Sex reversal is one of the characteristic properties of sexual plasticity in bony fishes wherein both natural and
Sex reversal induced sex change happens at various stages of life cycle in different species. Sex determination in gonochoristic
Sequential hermaphrodite species is genetically regulated, wherein the same sex is retained throughout their life span whereas hermaph­
Sex steroids
rodites change their sex during development or adulthood. In sequential hermaphrodites, serial sex change
Gonadal transdifferentiation
occurs at different points of life cycle. Concurrently, synchronous hermaphrodites function as both the sexes
Sexual dimorphism
Teleost during spawning. Other variables like temperature, pH and social factors can trigger sex reversal in teleost. Sex
reversal through gene mutations and chemicals/hormones, including sex steroids, can be induced mostly at early
developmental stages but natural sex reversal can occur at any time. Sex reversal mechanism shows morpho­
logical to molecular changes, which are ideal for identification of sex-specific gene markers. In fact, gonadal
transdifferentiation occurs at the molecular level through differential expression of transcription factors and
steroidogenic enzyme genes vis-a-vis hormones, thereby imparting phenotypic or structural changes. In addition,
brain shows sexual dimorphism which is mostly consequential to gonadal sex development and occasionally
either causative. The major breakthrough in this line is the identification of sex determining genes such as dmy/
dmrt1Yb, gsdfY, sox3 in the Japanese medaka and amhY in Patagonian pejerrey. Incidentally, the induction of
mono-sex population by favouring one sex due to sex-specific differences in growth is an important economic
boom for aquaculture. This review comprehensively highlights key molecular factors involved in natural and
induced sex reversal conditions to illustrate teleostean sexual plasticity and its application perspectives.

regulatory mechanisms leading to endocrine sex differentiation remain

1. Introduction
One of the fascinating properties exhibited by bony fishes is the ex­
istence of various reproductive strategies in terms of sexuality. Sex
determination in teleost is a crucial event comprising a bipotential
gonad to develop either into an ovary or testis, but the underlying
mechanisms vary differently among taxa (Devlin & Nagahama, 2002;
Hayes, 1998). Fishes exhibit gonochorism like most vertebrates,
whereby the sexual fate of an individual is majorly determined by ge­
netic, environmental and hormonal interactions (Volff, 2002). They
develop into either male or female and retain the same sex throughout
the life. Unlike other vertebrates, few fishes are referred to as her­
maphrodites, wherein they function as both male and female during the
same spawning period (Helfman, Collette, & Facey, 1997, p. 544). In
contrast to this, sequential hermaphrodites were found to function as a
male and a female at different stages of life (Warner, 1988). Despite of
sexual plasticity and various reproductive patterns, the underlying
conserved (Kobayashi, Nagahama, & Nakamura, 2013). In this process,
sex reversal becomes an intriguing phenomenon most commonly
observed in certain groups of teleost. In all mammals, SRY (sex deter­
mining region Y in all mammals) is the first sex determining gene
discovered that is sufficient for testicular development (Koopman,
Gubbay, Vivian, Goodfellow, & Lovell-Badge, 1991; Koopman, Mün­
sterberg, Capel, Vivian, & Lovell-Badge, 1990; Sinclair et al., 1990).
Incidentally, the sry-like genes could not be isolated in fish, yet fishes
express certain master genes which regulate the formation of gonads
that are gender-specific. Among non-mammalian vertebrates, dmy or
dmrt1b which is a duplicate copy of doublesex and mab-3 related factor 1
(dmrt1) on the Y chromosome, was the first sex determining gene
identified in the Japanese medaka, Oryzias latipes and later in
O. curvinotus, which is associated with testicular differentiation (Mat­
suda et al., 2002, 2003; Nanda et al., 2002). But in other species of
medaka, O. luzonensis gsdfY was the sex determining gene (Myosho et al.,
2012). In line with this, sex determining genes identified so far in fishes

* Corresponding author. Department of Animal Biology, School of Life Sciences, University of Hyderabad, P.O. Central University, Hyderabad, 500046, India.
E-mail addresses: bsksl@uohyd.ac.in, senthilkumaranbalasubramanian@gmail.com (B. Senthilkumaran).

https://doi.org/10.1016/j.aaf.2022.02.007
Received 29 December 2021; Received in revised form 15 February 2022; Accepted 26 February 2022
Available online 17 March 2022
2468-550X/© 2022 Shanghai Ocean University. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Tenugu and B. Senthilkumaran Aquaculture and Fisheries 7 (2022) 525–539

List of abbreviations foxl2 forkhead box protein L2

FSH follicle stimulating hormone
11b-h 11b-hydroxylase Fshr follicle stimulating hormone receptor
11-KT 11-ketotestosterone Gdnf glial cell line-derived neurotrophic factor
5-HT serotonin gfrα-1 glial cell line-derived neurotrophic factor family receptor
5-HTP 5-hydroxy tryptophan GnRH gonadotropin-releasing hormone
Ad adrenosterone Gsdf gonadal soma-derived growth factor
ad4bp/sf-1 adrenal-4-binding protein/steroidogenic factor 1 GTH gonadotropin
AI Aromatase inhibitors hCG human chorionic gonadotropin
amh anti-Müllerian hormone HHG hypothalamo-hypophyseal-gonadal
amhr2 anti-Müllerian hormone receptor type 2 hsd11b2 hydroxysteroid 11β-dehydrogenase 2
amhy Y chromosome-linked anti-Müllerian hormone hsd3b hydroxy-delta-5-steroid dehydrogenase 3 beta
ar androgen receptor LH luteinizing hormone
CA catecholamine Lhr luteinizing hormone receptor
cAMP cyclic adenosine monophosphate Mas masculinization
cyp11a1 cytochrome P450 family 11 subfamily a polypeptide1 MT 17α-methyltestosterone
cyp19a aromatase NE norepinephrine
cyp19a1 cytochrome P450 family 19 subfamily a polypeptide 1 NPY Neuropeptide Y
DA dopamine PGC PGCs progenitor germ cells
DMY Y-specific DM-domain POA-H preoptic area-hypothalamus
DMY/dmrt1bY doublesex and mab-3-related transcription factor 1 ptx pentraxin
dpf days post fertilization sox SRY-box transcription factor
dph days post hatch sox9 SRY-box 9
E2 17β-estradiol T testosterone
EE2 ethynylestradiol th tyrosine hydroxylase
er estrogen receptor tph tryptophan hydroxylase
ET 17α-ethynyltestosterone

tend to vary from species to species, for example, amh-Y in the Pata­
gonian pejerrey, Odontesthes bonariensis, amhr2 in the pufferfish, Taki­
fugu rubripes, irf9y in the rainbow trout, Oncorhynchus mykiss and amh in
the Nile tilapia, Oreochromis niloticus (Cáceres et al., 2019; Hattori et al.,
2012; Kamiya et al., 2012; Yano et al., 2012). But, the evolutionary
conservation of several sex determining genes identified so far is still
unclear. These genes specifically regulate some downstream targets,
which are highly conserved among different species. Some of the genes
involved in gonadal development include doublesex/mab3-related
transcription factors (dmrt), Wilms’ tumour suppressor gene (wt1),
anti-Müllerian hormone (amh), SRY-box 9 (sox9), aromatase (cyp19) and
steroidogenic factor 1 (Ad4BP/sf-1) were identified in the autosomes of
several species. In most fishes, sex is determined through factors from
somatic as well as sex chromosomes, yet the sexual fate is susceptible to
hormones as well as environmental factors leading to sex reversal. In a
holistic view, overriding of genetic factors through hormone or envi­
ronmental influence is likely in teleosts.
Sex reversal property was first demonstrated by the Japanese sci­
entist, Yamamoto in medaka through sex reversing the genotypic female
to male phenotype and genotypic male to female phenotype (Yama­
moto, 1953; 1958). Later, it was postulated that the sex steroids act as
natural female and male sex inducers, which led to a framework in
research to find the underlying mechanisms of sex change that have
been continued till date (Yamamoto, 1969). In addition, aromatase
blockers like fadrozole were often used for sex reversal in a few teleosts
(Afonso, Wassermann, & Terezinha de Oliveira, 2001; Nakamura,
Kobayashi, Miura, Alam, & Bhandari, 2005; Zhou & Gui, 2010). Taken
together, the sex determination and differentiation, as well as sexual
plasticity in response to sex steroids and environmental factors, is a
complex process. The sex reversal phenomenon observed during in­
duction by steroid hormones is perceived only during the critical period
of gonadal differentiation. More specifically, sex steroids under natural
and induced conditions mediate sex change either to male or female in
most of the teleost in a particular time frame. The environmental factors,
including temperature, pH and social factors show an impact on sex
determination/differentiation in most of the teleosts (Fernandino, Hat­
tori, Moreno Acosta, Strüssmann, & Somoza, 2013). Additionally,
certain endocrine disruptors affect sex determination/differentiation
and reverse differently. This review will aim to highlight different as­
pects including sex reversal induced by various steroid hormones,
environmental factors and ultimate use of generating monosex popula­
tion through hormonal treatment followed by genetic cross as well as
brain sex dimorphism exhibited by few teleost which were categorized.
2. Sexual development: Morphological changes during normal
gonadal development including sex reversal
Sexual development is a conserved process in most of the vertebrates,
which define particular events that specifically occur during gonadal
development by allowing the expression of genetic sex into its appro­
priate phenotype (Devlin & Nagahama, 2002; Piferrer, 2001; Piferrer &
Blázquez, 2005). The molecular mechanisms leading to females and
males exhibits wide diversity among vertebrates and the cascade of
events during sex differentiation seems relatively conserved (Nagahama,
2005). The sex steroids, mainly, androgens and estrogens play a very
important role in regulating sex differentiation process (Piferrer &
Guiguen, 2008). It commences with the migration of primordial germ
cells, followed by their colonization into genital ridge forming gonadal
primordium and extends the first process of gametogenesis with the
release of gametes upon eventful completion. Due to sexual plasticity,
some fishes act as functional males and females during their life-time,
referred to as hermaphrodites compared to non-sex-changing species,
i.e., gonochoristic which retain only one sex throughout their life. Two
terms have been employed for the classification of gonochoristic species
by Yamamoto (1969), referred to as (1) differentiated gonochorists
where the undifferentiated gonad directly develop into an ovary or a
testis during early gonadal development as observed in the European
seabass, Dicentrarchus labrax, the common carp, Cyprinus carpio and the
coho salmon, Onchorynchus kisuch (Blázquez, Zanuy, Carrillo, & Piferrer,
1998; Komen, De Boer, & Richter, 1992; Piferrer & Donaldson, 1989)

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S. Tenugu and B. Senthilkumaran
and (2) undifferentiated gonochorists, in which all the individuals first
develop gonads containing oocytes which is termed as ovarian differ­
entiation. Later, the oocytes undergo degeneration through apoptosis in
half of the population, followed by masculinization of the gonad pro­
ceeding to form an intersexual gonad that eventually develops into
normal testis (Maack & Segner, 2003). This phenomenon is termed as
juvenile hermaphroditism and was reported in O. masou and Gambusia
affinis (Koya, Fujita, Niki, Ishihara, & Miyama, 2003; Nakamura, 1984).
But in a few species, juveniles possessing a bipotential intersex gonad
was found to develop into either ovary or testis as observed in the
serranid, Epinephelus striatus, the Japanese eel, Anguilla japonica and the
European eel, A. anguilla (Beullens et al., 1997; Colombo & Grandi,
1995; Sadovy & Colin, 1995). Hermaphroditism is a naturally occurring
phenomenon observed in most of the species and categorized as simul­
taneous or sequential (Shapiro, 1990; Yamamoto, 1969). In simulta­
neous species, the individuals possess both male and female gonadal
tissues where both function together. Sequential hermaphrodites are
categorized into protandrous, which initially mature as males and pro­
togynic that matured as females (Ross, 1990). In some protogynous
species such as the bluehead wrasse, Thalassoma bifasciatum, few in­
dividuals differentiate directly into males whereas others first pass
through the condition of being functionally females (Munday, Buston, &
Warner, 2006; Munday, Wilson White, & Warner, 2006). These species
referred to as diandric protogynous which is a rare property observed in
protoandric species (Devlin & Nagahama, 2002). In addition, certain
species like the rubble gobiid fish, Trimma okinawae have the ability to
undergo serial sex change based on the social colonization behavior.
This has been well demonstrated wherein serial sex change of dominant
female to male and vice-versa occurred after the introduction of the
dominant male in an artificial culture condition (Sunobe & Nakazono,
1993). These serial sex changing fish have differential expression
pattern of gonad-specific genes. This was the first known teleost where
bi-directional sex change was observed which became advantageous
wherein a male was forced to become subsidiary, ensuing to take over
the social unit by a larger male. Other species such as the saddleback
wrasse, T. duperrey also undergo protogynous sex change where the
individuals initially mature as females or males. Later, under social
conditions initial phase (IP) female or male fish become terminal phase
(TP) males. But in this species, females housed with IP males undergo
sex change to become TP males which have high circulating levels of
11-KT and spawn individiually with large female successfully (Morrey,
Nagahama, & Grau, 2002). Conversely, females housed with TP males,
inhibits sex change but helps in the maintenance of ovarian function and
likelihood of successful pair spawning with immediate proximity fe­
males. Therefore, under social conditions females change their sex along
with gonadal phenotype compared to males which are only restricted in
regulating sex change and maintain ovarian function in females
(Hourigan, Nakamura, Nagahama, Yamauchi, & Grau, 1991). In such
species, during sex change, the ovaries which possess undetectable
testicular tissue in females were fully reorganized to a functional testis
(Nakamura, Hourigan, Yamauchi, Nagahama, & Grau, 1989). But in the
yellowtail clownfish, Amphiprion clarkii, the dominance of the sex
change depends on the size. For example, normally female is a dominant
and male is the second-largest member in that population based on size.
In the absence or death of the female, sex change of male to female
occurs, thus, ultimately leading to female dominance (Fricke & Fricke,
1977). The sex steroid hormones such as estrogens and androgens
induced sex change in several teleost which are categorized as key
regulators (Godwin & Thomas, 1993). Thus, due to this sexual plasticity,
the underlying mechanisms involved during sex change make it more
prominent to identify genes contributing to sex differ­
entiation/determination. In the first instance, sex steroids seem to play
an essential role in evoking sex reversal.
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Aquaculture and Fisheries 7 (2022) 525–539
3. Sex steroids causing sex reversal
Even though the sex determination in fishes is under genetic regu­
lation, the external factors such as temperature, pH, social behavior
induce sex reversal in most of the fishes, where the process of sex
determination, as well as differentiation has already been well estab­
lished (Bushmann & Burns, 1994; Lowe & Larkin, 1975; Pandian &
Koteeswaran, 1998; Strüssmann, Calsina Cota, Phonlor, Higuchi, &
Takashima, 1996). Additionally, in fishes where the sex differentiation is
not yet completed, manipulation of gonadal sex through the adminis­
tration of sex steroids via diet, immersion, injection or through im­
plantation technique is possible (Devlin & Nagahama, 2002; Frisch,
2004; Nagahama, 2002; Pandian & Sheela, 1995). Sex reversal through
endocrine mediated techniques is well applied for the production of
monosex populations. Steroid hormones are widely used to control and
manipulate the sex of the fish (Baroiller, Guiguen, & Fostier, 1999; Borg,
1994; Lee et al., 2000; Nakamura et al., 1989). This practice was mostly
used in teleosts, among which tilapia and salmonids have received
utmost attention. Sex reversal has been limited to only few species such
as the channel catfish, Ictalurus punctatus and the African catfish, Clarias
gariepinus by giving steroid hormone through dietary supplementation
or exposure in water (Galvez, Mazik, Phelps, & Mulvaney, 1995; Goudie,
Redner, Simco, & Davis, 1983; Liu, Yao, & Wang, 1996; Raghuveer &
Senthilkumaran, 2009). In order to advance the maturation in the cat­
fish, C. gariepinus, human chorionic gonadotropin (hCG) induction was
performed by implantation of osmotic pump during off breeding season
and expression of several steroidogenic enzymes, transcription factors
and hormonal levels were measured (Murugananthkumar, Prathibha,
Senthilkumaran, Rajakumar, & Kagawa, 2017). However, C. batrachus
and C. gariepinus show distinct difference because of the seasonal pattern
variance exhibited and hence, these species seem to be the best model to
study any kind of a seasonal influence or endocrine manipulation
(Rajendiran et al., 2021; Senthilkumaran & Kar, 2021). In some studies
of the Asian stinging catfish, Heteropneustes fossilis when eggs were
treated with 17α-methyltestosterone (MT) and 17α-ethynyltestosterone
(ET) it produced males and upon treatment with 17β-estradiol (E2) and
diethylstilbestrol it produced females (Haniffa, Sridhar, & Nagarajan,
2004). This sex reversal was amenable as they show sex change at the
time of hatching. This feminization is mainly due to the conversion of
androgens to estrogens by the cyp19a enzyme. Similarly, this feminizing
effect was also found in Salmo gairdneri and occurred only at higher
doses of MT treatment (Solar, Donaldson, & Hunter, 1984).
Sex-change is majorly triggered by several steroids such as E2, 11-
ketotestosterone (11-KT) and Testosterone (T). E2 is one of the most
dominant estrogen amongst protandric species that is associated with
sex change in most of the teleosts (Kime, 1993). E2 is a predominant
feminizing sex steroid that can induce permanent sex transition in some
teleosts (Chang & Lin, 1998; Lee et al., 2000) and also increase E2
production concurrently through progression of natural sex reversal in
several species (Godwin & Thomas, 1993; Guiguen, Jalabert, Benett, &
Fostier, 1995; Nakamura et al., 1989). In contrast, 11-KT is the pre­
dominant sex steroid which is related to sex change to masculinization
in most of the protogynous species, whereby permanent sex transition
was observed upon treatment of the correlate in many species (Cardwell
& Liley, 1991; Grober, Jackson, & Bass, 1991; Higa, Ogasawara, Saka­
guchi, Nagahama, & Nakamura, 2003; Kroon & Liley, 2000). Similar to
E2, 11-KT levels also showed a progressive increase in synthesis during
natural sex change to masculinization in many species (Bhandari,
Komuro, Nakamura, Higa, & Nakamura, 2003; Nakamura et al., 1989).
11-KT male specific and E2 female specific were found to be the domi­
nant products in the incubates of the gonadal tissues that undergo
transition (Borg, 1994; Lee et al., 1995; Yeung, Chen, & Chan, 1993).
The function of 11-KT in protogynous species is antithetical to that of E2
in protandric species facilitating as switches between female and male
phenotypes (Hunter & Donaldson, 1983; Pandian & Sheela, 1995;
Piferrer, 2001; Piferrer, Baker, & Donaldson, 1993). In transitional
S. Tenugu and B. Senthilkumaran
A. melanopus, no apparent E2 levels were evident until after oogonial
proliferation indicating E2 is not required for initiating sex change in this
species (Godwin & Thomas, 1993). However, in some other species very
low or undetectable levels of 11-KT were observed during transitional
sexual phases that led to a point whether 11-KT involved in sex change
or else mediated through different combination of steroids (Kime, 1993;
Kroon, Munday, & Pankhurst, 2003; Yeung & Chan, 1987). In several
studies of hermaphrodite species, similar to 11-KT, T also play a role
during sex change by maintaining its levels independent to the sexual
stage, indicating T not directly involved during transitions (Cardwell &
Liley, 1991; Guiguen, Jalabert, Thouard, & Fostier, 1993; Nakamura
et al., 1989). Interestingly, administration T, MT and testosterone pro­
pionate induced sex change in few protogynous species (Glamuzina,
Glavić, Skaramuca, & Kožul, 1998; Hassin et al., 1997; Kuo, Ting, & Yeh,
1988; Lee et al., 1995; Tan-Fermin, Garcia, & Castillo, 1994; Yeh, Kuo,
Ting, & Chang, 2003), whereas in estuary grouper small doses of T has
stimulated ovarian development. In contrast, T or 5α-dihydrotestoster­
one in T. bifasciatum induced ovarian degeneration (Kramer, Koulish, &
Bertacchi, 1988), suggesting that sex change is not influenced by steroid
directly but indirectly affects the precursor’s availability for biosyn­
thesis. However, in most of the species, T shows ubiquitous presence
irrespective of the female or male phase. Thus the physiological effect
upon T administration majorly depends on enzymes, for example,
cyp19a or 11bh which are dominant during the time of treatment. The
distinct conversion of the substrates of T into androgens and estrogens
was corroborated in few studies when incubated with testicular and
ovarian tissues (Lee et al., 1995; Yeung et al., 1993). Incidentally, in
C. gariepinus MT treatment did not induce complete sex reversal in entire
population which is evident from the occurrence of intersex. On the
other hand, in the same species, E2 treatment induced almost complete
sex reversal (Raghuveer & Senthilkumaran, 2009).
Apart from classical steroids, non-classical steroids such as adre­
nosterone (Ad) are known to induce sex change in certain species such as
black-eye goby, Coryphopterus nicholsii, but this particular effect is more
likely due to the presence of 11-KT precursor, as receptors for Ad does
not exist (Kroon & Liley, 2000). Aromatase inhibitors (AI) such as
fadrozole and exemestane suppress the sex change observed during
natural sex reversal in protandric black porgy, Acanthopagrus schlegeli,
whereas induced sex change in other species such as protogynous
black-eye goby, C. nicholsii, honeycomb grouper, E. merra, threespot
wrasse, Halichoeres trimaculatus (Bhandari, Higa, Nakamura, & Naka­
mura, 2004; Kroon & Liley, 2000) indicating E2 dominance. Addition­
ally, E2 when co-administered with 11-KT or AI, also suppressed
sex-change in H. trimaculatus (Higa et al., 2003). Upon oral adminis­
tration of MT in carp underwent sex reversal from female to male which
was evaluated by using all female gynogenetic carp during sex differ­
entiation (Komen, Lodder, Huskens, Richter, & Huisman, 1989; Nagy,
Bercsényi, & Csányi, 1981). In another study, masculinization (mas)
mutant which is an autosomal sex-determining gene involved in testes
differentiation, induced sex reversal of male development in XX females
(Komen et al., 1992). In tilapia, MT administration induced masculini­
zation in XX larvae and treatment with AIs caused sex reversal of
functional males (Afonso et al., 2001; Kobayashi, Kajiura-Kobayashi,
Guan, & Nagahama, 2008; Kwon, McAndrew, & Penman, 2002; Naka­
mura, Kobayashi, Chang, & Nagahama, 1998; Ruksana, Pandit, &
Nakamura, 2010). However, estrogen treatment did not induce XY sex
reversal in tilapia as easily as androgen treatment in XX sex reversal
along with AIs whereas 17α-ethynylestradiol treatment from 4 to 6 days
post hatch (dph) resulted in complete sex reversal of XY with germ cells
proliferation similar to that of XX gonads (Kobayashi et al., 2008;
Kobayashi, Kajiura-Kobayashi, & Nagahama, 2003). Similarly, mascu­
linization effect is caused by AI was also observed in the Japanese
flounder, Paralichthys olivaceus, the Chinook salmon, O. tshawytscha and
the rainbow trout, O. mykiss (Guiguen et al., 1999; Kitano, Takamune,
Nagahama, & Abe, 2000; Piferrer et al., 1994).
In female breeding medaka, exposure of AI, the letrozole, affected
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Aquaculture and Fisheries 7 (2022) 525–539
oocyte development (Sun, Zha, Spear, & Wang, 2007). Ovarian trans­
differentiation was evident in female zebrafish upon AI treatment
wherein first testis-like tissues containing spermatozoa-like cells devel­
oped, which was followed by ovary retraction (Takatsu et al., 2013). Sun
et al. (2014) observed the differentiated ovary to undergo trans­
differentiation and become functional testis upon long-term AI treat­
ment causing functional sex reversal in tilapia. It was noteworthy that
the first morphological change of ovarian structure in this species was
observed at 20 dph (Kobayashi et al., 2008). In medaka, estrogen
treatment in XY males resulted in ovarian development while XX fe­
males upon treatment with androgens induced testis development,
causing sex reversal (Yamamoto, 1953). Incidentally, fertilized XY eggs
of medaka when immersed in water containing exogenous E2 induced
sex reversal of few genotypic males to functional females (Iwamatsu,
Kobayashi, Hamaguchi, Sagegami, & Shuo, 2005). However, neither
dmy nor the germ cells number was affected during the early gonadal
development indicating that the Japanese medaka seems not succumb­
ing to external E2 treatment during early gonadal sex differentiation
(Scholz et al., 2003; Suzuki, Nakamoto, Kato, & Shibata, 2005). The
killifish, Kryptolebias marmoratus capable of undergoing self-fertilization
showed skewness to male sex development of embryos after treatment
with MT (Kanamori et al., 2006).
4. Factors affecting sex reversal
4.1. Temperature
Temperature-induced sex reversal is one of the properties observed
in several teleost by triggering various candidate genes associated with
it. The first observation of temperature effect on sex reversal was found
in the Atlantic silverside, Menidia menidia, wherein warm fluctuating
temperature (17–25 ◦ C) treatment during larval development resulted in
male population (Conover & Kynard, 1981). Among the poeciliids and
cichlids families, the blackbelly limia, Poecilia melanogaster and um­
brella cichlid, Apistogramma borelli showed a significant effect when
larvae were incubated at a temperature range from 23 to 29 ◦ C, which
produced male broodstocks (Römer & Beisenherz, 1996). In medaka,
when embryos were exposed to the high water temperature of 34 ◦ C,
female to male sex reversal was evident, and this simple methodology
was used to produce XX males (Kobayashi, 2013; Sato, Endo, Yamahira,
Hamaguchi, & Sakaizumi, 2005). The genotypic females (XX) of Hd-rR
strain in medaka exhibited sex reversal into male phenotype upon
exposure of fertilized eggs at embryonic stages 5–6 to the temperature
between 17 and 34 ◦ C until hatching, and most of them showed 100%
sex reversal at 34 ◦ C (Hattori et al., 2007). But this thermal manipulation
for inducing sex reversal was ineffective at stage 36 which is at middle
embryogenesis stage. But in another study, when Hd-rR and green
fluorescent protein transgenic medaka were exposed to 32 ◦ C at em­
bryonic stage 25 caused sex reversal suggesting that the process of
gonadal sex differentiation induced by high temperature is limited only
before the occurrence of morphological sex differentiation stage (Selim,
Shinomiya, Otake, Hamaguchi, & Sakaizumi, 2009). In addition to this,
high temperature induced expression of dmrt1 in females after stage 36
during embryonic development (Hattori et al., 2007), whereas in normal
males, it is expressed in XY gonads after 10 to 20 dph (Kobayashi et al.,
2004). Elevated temperature treatment of 32–34 ◦ C in tilapia, produced
an increased number of males in XX progeny whereas a decreased
number of females in XY and YY progenies (Abucay, Mair, Skibinski, &
Beardmore, 1999; Baroiller, Chourrout, Fostier, & Jalabert, 1995; Kwon
et al., 2002). The thermosensitivity period in this species ranged from 10
to 20 days post fertilization (dpf) or 40 dpf (Baroiller, D’Cotta, & Sail­
lant, 2009). Decreased expression of cyp19a1 and foxl2 with elevated
expression of dmrt1 was evident in XX larvae when exposed to a high
masculinizing temperature in tilapia (Baroiller, D’Cotta, & Saillant,
2009; d’Cotta et al., 2001; Poonlaphdecha et al., 2013). Interestingly,
the dmrt1 suppresses the cyp19a1a transcription by repressing the
S. Tenugu and B. Senthilkumaran
activity of Ad4BP/sf1 dependent female pathway during sex reversal
upon MT treatment in tilapia (Wang et al., 2010). Similarly, decreased
cyp19a1a expression was observed upon high masculinizing tempera­
ture exposure in the European sea bass, the Japanese flounder, the
Japanese medaka and zebrafish (Kitano, Hayashi, Shiraishi, & Kamei,
2012; Kitano, Takamune, Kobayashi, Nagahama, & Abe, 1999; Nav­
arro-Martín et al., 2011; Uchida, Yamashita, Kitano, & Iguchi, 2004).
But the underlying molecular mechanism relating temperature with
cyp19a1a expression is yet to be deciphered. One of the mechanisms
linking the temperature in sex ratio shift is the epigenetic modification
observed in the study using the European sea bass model in which of
increased methylation of cyp19a1a promoter in females by temperature
decreased its expression in masculinized fish during sex reversal (Nav­
arro-Martín et al., 2011). This is due to the prevention of binding of
Ad4BP/sf-1 and foxl2 to the promoter sites and in turn blocking
cyp19a1a transcriptional activation (Wang et al., 2007). The similar
epigenetic modification was also observed during temperature mediated
sex reversal in zebrafish by methylation and decreased expression of
cyp19a1a, esr1 and sox9b as well as enrichment of cAMP-responsive
element-binding proteins were observed (Han et al., 2021). In the Jap­
anese flounder, temperature exposure 36 ◦ C induced sex reversal from
XX female to XX males with increased gsdf expression and inhibition of
germ cell proliferation leading to testis development (Yang et al., 2019).
The African catfish, C. gariepinus, upon 36 ◦ C exposure, showed a
masculinization effect when treated for at least 3days between 0 and
23dph and often skewed towards 100% male phenotypes when applied
from 6-8dph (Santi et al., 2016). In contrast, full masculinization was
observed in common carp when larvae were exposed to 36 ◦ C, partic­
ularly between 7 and 13 dph (Biswas et al., 2021).
The elevated temperature leads to stress and increased the level of
cortisol during sex reversal has also received the most attention on
reproduction (Consten et al., 2002; Mommsen, Vijayan, & Moon, 1999;
Schreck, 2010). The plasma levels of cortisol and androgens were
observed in few species during the sex determination and differentiation
period. For example, the cortisol levels increased in the pejerrey when
larvae reared in warm and male-inducing temperatures compared to
that of low temperature (Hattori et al., 2009). Additionally, when
treated with cortisol and dexamethasone, agonist, male-biased sex ratios
were observed when reared under intermediate temperatures. Interest­
ingly, very high levels of 11-KT and T were evident (Hattori et al., 2009).
The three possibilities of inducing masculinization may include (i)
cortisol inhibiting cyp19a1a expression, (ii) cortisol reducing the num­
ber of progenitor germ cells (PGC) and, (iii) cortisol affecting 11-KT
synthesis. The first possibility was evident in the Japanese flounder
and pejerrey where cortisol induced masculinization and cyp19a1a
downregulation were seen (Hattori et al., 2009; Yamaguchi, Yoshinaga,
Yazawa, Gen, & Kitano, 2010). The depletion of number of PGCs and
their proliferation during masculinization was observed in medaka
(Tanaka, Saito, Morinaga, & Kurokawa, 2008). Increased incidence of
temperature dependent apoptosis in gonadal primordia during testicular
differentiation was documented in zebrafish, pejerrey and medaka (Ito,
Takahashi, Yamashita, & Strüssmann, 2008; Saito et al., 2007; Saito &
Tanaka, 2009; Uchida, Yamashita, Kitano, & Iguchi, 2002). An increase
in the levels of androgens was also reported in several teleosts with
masculinizing effect (Devlin & Nagahama, 2002). This ultimately in­
dicates the inhibition of cyp19a1a expression followed by apoptosis
might be a consequence for an increase in the production of androgens
to reinsure that cortisol can trigger masculinization in teleost upon high
temperature exposure.
4.2. Hypoxia
Hypoxia is a condition of the presence of low levels of dissolved
oxygen concentration in water and one of the factors affecting sex dif­
ferentiation in fish. Hypoxia is more likely perceived as a stressor by
fishes as with other environmental factors, specifically during the early
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Aquaculture and Fisheries 7 (2022) 525–539
stages of development. For example, a male-biased sex ratio was
observed in zebrafish when reared under hypoxic conditions compared
to normoxic (Shang & Wu, 2004; Shang, Yu, & Wu, 2006). This is due to
the modulation of the expression of steroidogenic enzyme genes, which
alters T and E2 balance (Pollock, Dubé, & Schryer, 2010; Wu, Zhou,
Randall, Woo, & Lam, 2003; Yu et al., 2012). It was reported that the
African cichlid Egyptian mouth-brooder, Pseudocrenilabrus multicolor
victoriae exhibited higher T levels when exposed to hypoxic conditions
compared to normal oxygenated fish however, E2 levels were not
affected (Friesen, Aubin-Horth, & Chapman, 2012). An increase in
cortisol followed by hypoxic conditions was evident during the early
stages of development in rainbow trout, suggesting that all are interre­
lated and majorly active during this particular period (Fuzzen,
Alderman, Bristow, & Bernier, 2011). In the Atlantic croaker, hypoxia
decreased tryptophan hydroxylase (TPH), cyp19a1b expression in the
hypothalamus. In vivo treatment with AI, 1,4,6-androstatrien-3,17-dione
also decreased TPHs, 5-hydroxy tryptophan (5-HTP), serotonin (5-HT)
and TPH activity (Rahman & Thomas, 2013). In the same study, E2
treatment partially restored TPH activity, 5-HTP, 5-HT, TPHs contents in
hypoxia-exposed fish, indicating the role of estrogens in controlling
neuronal responses to hypoxic conditions in aquatic vertebrates (Rah­
man & Thomas, 2013). Combination of environmental stress of hypoxia
and xenobiotic exposure of polychlorinated biphenyl mixture (Aroclor
1254) in the Atlantic croaker decreased TPH activity that accompanied
with fall of 5-HT in hypothalamus and gonadotropin-releasing hormone
(GnRH1) content in preoptic area-hypothalamus (POA-H) region (Khan
& Thomas, 2000). This was further associated with a reduction in LH
secretion and gonadal development which has been well-reviewed
(Khan & Thomas, 2001; Rahman, Khan, & Thomas, 2011). 17, 20β,
21-trihydroxy-4-pregnen-3-one, a progestin hormone that induce
gamete maturation, were significantly decreased under hypoxic condi­
tions in both sexes of the Atlantic croaker leading to impairment in
gamete maturation (Thomas & Rahman, 2009). Hypoxia is also associ­
ated with endocrine dysfunction in this species by decreasing endocrine
indicators of the estrogen signalling pathway, that regulate vitellogenin
production which is a precursor for growing oocytes leading to a
reproductive failure (Thomas, Rahman, Kummer, & Lawson, 2006).
4.3. pH
Other environmental factor affecting on sex ratio include pH, mostly
studied in poeciliids and chiclids species. Even though the effect of pH is
less prominent, but in common, acidic or low pH 5–6 exposure Pelvi­
cachromis subocellatus, P. pulcher, P. taeniatus, A. borelli, A. caucatoides,
and Xiphophorus helleri skewed towards the appearance of males while a
high pH value of 7 skewed towards the occurrence of females (Rubin,
1985; Sullivan & Schultz, 1986). The sex ratio of 1:1 of males and fe­
males was found when P. pulcher was exposed to intermediate pH (6.10)
(Rubin, 1985). In contrast, the other species, Poecilia sphenops higher
proportion of females was evident when combined with temperature
(30 ◦ C) and pH 6 or 7 exposure. At the same time male ratio increased
when exposed to 22 and 26 ◦ C with pH 8 depicting opposite gender-bias
effect (Benjamín Barón, Fernando Bückle, & Espina, 2002). Exposure of
various environmental stress factors and different hormonal treatment
and expression of genes in depicting gonadal fate in various teleosts are
illustrated in Table 1.
4.4. Social interactions
Population density is an important social factor effecting sex deter­
mination in few teleosts. This appeared to be more prominent for sex
determination in Anguilliformes (Beullens et al., 1997; Davey & Jelly­
man, 2005; Degani & Kushnirov, 1992; Holmgren, 1996; Krueger &
Oliveira, 1999; Tzchori, Degani, Hurvitz, & Moav, 2004). For example,
in the American eel, A. rostrata, low population density was interrelated
with a high number of females, whereas male-biased sex ratio was
S. Tenugu and B. Senthilkumaran Aquaculture and Fisheries 7 (2022) 525–539

Table 1
Exposure of environmental stress factors and different treatment in teleost depicting gonadal fate. A downward arrow pointing indicates decrease in hormone con­
centration, gene expression, enzymatic activity, an upward arrow indicates increase in these parameters, equal symbol depicts normal expression. “NS”: not studied.
Species Environmental Response on Steroids levels/ Physiological Response/ References
Stress factor/treatment transcription factors/steroidogenic Event
enzyme genes related to gonad

Anguilla anguilla Low density high ↑ cyp19a1a Feminization Tzchori et al. (2004)
density, cortisol ↑ cortisol, ↑11-KT Male-skewed population
treatment
Apistogramma sp T, acidic pH NS Male induced population Römer and Beisenherz (1996)
Clarias gariepinus MT = dmrt1, sox9a, foxl2, cyp19a1(Ova- Male-skewed population, Raghuveer and Senthilkumaran (2009)
testis); Intersex (Ova-testis)
= dmrt1 and sox9a (testes); = foxl2
and cyp19a1 (ovary)
Cyprinus carpio MDHT ↑ sox9a/b, ↑ sox30, ↑lhr Monosex induction Anitha & Senthilkumaran, 2020; Anitha, &
E2 ↓sox9a/b, ↓sox30, ↑ sox19, Senthilkumaran, 2022; Gupta & Senthilkumaran,
↑ cyp19a1a, ↑ fshr, ↑ ptx 2020
Danio rerio T (high) ↓ cyp19a1a Female to male sex reversal, Abozaid, Wessels, & Hörstgen-Schwark, 2012;
Hypoxia ↑ T/E2 ratio, ↑ cyp19a1a, apoptosis of PGCs Uchida et al., 2002, 2004
↑ cyp19a1b, ↑cyp17, ↑3β-hsd, Male-skewed population, Baroiller, D’Cotta, & Saillant, 2009; Shang et al.,
↑ cyp11a apoptosis induction of PGCs 2006; Yamamoto, 1969
Dicentrarchus labrax T (high) ↓ cyp19a1a Masculinization. cyp19a1a Blazquez, Navarro-Martín, & Piferrer, 2009;
promoter hypermethylation Navarro-Martín et al., 2011; Pavlidis et al., 2000
Odontesthes bonariensis T (high), cortisol ↑ cortisol,↑11-KT, ↑ T, Male-skewed population, Fernandino et al., 2011; Blázquez & Somoza, 2010;
treatment ↑ amh,↓ cyp19a1a, ↑ dmrt1, apoptosis of germ cells Strüssmann, Kitahara, & Amashita, 2008; Hattori
↑ hsd11b2, ↑ fshr et al., 2009; Shinoda et al., 2010
Oreochromis niloticus T (high) ↓ cyp19a1a Induced masculinization Baroiller et al. (1995)
Oryzias latipes T (high), cortisol ↑ cortisol, ↑ gsdf, ↓ fshr, Inhibition of PGCs Hattori et al., 2007; Hayashi et al., 2010; Selim et al.,
treatment ↓ cyp19a1a proliferation 2009
E2 + cortisol ↓ cortisol, ↑ cyp19a1a, ↓ gsdf, Rescued masculinization Kitano et al. (2012)
E2 + T (high) ↓ cortisol, ↑ fshr and cortisol levels
Metyrapone (cortisol Inhibition of
synthesis inhibitor) masculinization
Paralichthys olivaceus T (high) ↓ foxl2, ↓ cyp19a1a, ↑ cyp26b1 Delayed meiotic initiation in Kitano et al., 1999; Yamaguchi & Kitano, 2012;
Cortisol treatment ↑ cortisol, ↓ foxl2, ↓ cyp19a1a germ cells Yamaguchi et al., 2010
Male induced population
Pseudocrenilabrus Hypoxia ↑ T/E2 ratio Male-skewed population, Friesen et al. (2012)
multicolor victoriae apoptosis of germ cells

induced by high population density in A. japonica (Davey & Jellyman,
2005; Krueger & Oliveira, 1999). Social factors such as size also affects
the sex differentiation in Cichlasoma citrinellum whereby larger fishes
during the juvenile stage mature into males (Francis & Barlow, 1993).
The interaction between growth rate as well as density are essential as
both are associated with sex determination (Davey & Jellyman, 2005).
Representation of outcome of sequencial hermaphrodites, environ­
mental factors steroid hormones, as well as monosexpopluation per­
formed in various species were depicted in Fig. 1.
5. Brain sex dimorphism
Fish retain large plasticity on sex reversal that was evident in the
brain and also exists this reversibility even during adulthood (Godwin,
2010). Brain sex differentiation in mammals and birds usually occurs
during embryonic development which are controlled by gonadal ste­
roids as well as genes regulating sex chromosomes, and epigenetic
modifications (McCarthy & Arnold, 2011). In teleosts, brain sex
dimorphism follows gonadal sex and this may either be a consequential
or causative phenomenon. Nevertheless, sexually dimorphic genes sexes
at the level of brain serve as a gene marker to understand sex reversal. In
non-sex reversal fish like goldfish, gender specific sexual behavior can
be induced through hormonal treatment illustrating the dominance of
gonadal sex over brain sex (Kobayashi, Saoshiro, Kawaguchi, Hay­
akawa, & Munakata, 2013).
5.1. Brain cyp19a1b and estrogen receptors
The brain cyp19a1b gene is involved as the feedback loop in regu­
lating the steroid production by kisspeptin and hypothal­
amo–hypophyseal–gonadal (HHG) axis (Hofmann, 2006). The rainbow
trout depicted elevated cyp19a1b expression in the brain of
differentiating males (Vizziano-Cantonnet et al., 2011). Whereas in
tilapia, upon exposure to 35 ◦ C, the expression of cyp11a1b was
decreased in genetic females and still lower in genetic males than those
found in masculinized females (D’cotta, Fostier, Guiguen, Govoroun, &
Baroiller, 2001). In another study on tilapia, XY and YY sex reversal into
females resulted in increased expression of cyp19a1b which was
dependent on ethynylestradiol (EE2) dosage along with increased E2 and
T levels (Gennotte, Mélard, D’Cotta, Baroiller, & Rougeot, 2014).
Increased cyp19a1b expression was evident in masculinized XX females
of tilapia along with high estrogen receptor-α (erα) and erβ expressions
upon temperature (27 ◦ C) treatment. Increased expression of cyp19a1b,
erα and erβ was observed in tilapia upon MT treatment in 10 and 20 dph
(Tsai, Wang, & Fang et al., 2001b). In contrast to this, increased
expression of cyp19a1b and erα was evident upon E2 treatment between
0 and 10 dph (Tsai, Wang, & Fang, 2001). Additionally, high tempera­
ture induced testicular differentiation after 10 dph in tilapia whereas
low temperature before 10 dph resulted in ovarian differentiation and
within this thermosensitive period both cyp19a1b and erα were down­
regulated relating brain feminization (Tsai, Chang, Wang, & Chao,
2003). In medaka brain, esr1 mediates male-biased expression, sug­
gesting its role in masculinization whereas esr2β and arβ are associated
with feminization (Hiraki et al., 2012). The same study depicted the
expression of female-specific estrogen and androgen receptors that are
activated and inhibited by estrogens and androgens, respectively. In the
pejerrey, cyp19a1b expression was evident in the brain at male pro­
ducing temperature before the sex differentiation onset (Strobl-Mazzulla
et al., 2008). Sex reversal was not evident when adult females were
treated with AI in the African cichlid Astatotilapia burtoni, however,
partial masculinization was noticed in steroid level changes, body shape,
appearance, colour, alterations in brain gene expressions that affected
sexual behavior indicating estrogenic influence in juveniles (Göppert
et al., 2016).

530
S. Tenugu and B. Senthilkumaran
Fig. 1. Schematic representation illustrating outcome of sequencial hermaphrodites, steroid hormones, environmental factors as well as monosexpopluation. Note:
References for these with respect to species has been covered in the bibliography of review.
5.2. GnRH why are hormones released on the first place?
Hormones released from the HHG axis regulate various reproductive
events which lead to fertility by regulating steroidogenesis through
feedback at the level of the pituitary and brain. GnRH is known to be a
hypothalamic decapeptide neurohormone majorly involved in repro­
duction by stimulating the release of gonadotropins, follicle stimulating
hormone (FSH) and luteinizing hormone (LH) by the pituitary gland,
that in turn regulates steroidogenesis and gametogenesis (Ando, Hew, &
Urano, 2001; Ando & Urano, 2005; Gomes, Costa, & Borella, 2013; Kah
et al., 2007; Maruska & Fernald, 2011; Yaron et al., 2003; Zohar,
Munoz-Cueto, Elizur, & Kah, 2010). GnRH exists in multiple forms
which has resulted through genome duplication (Powell et al., 1994).
Species specific and other forms of GnRH localized in various brain re­
gions were found to play a role in reproduction, neuromodulation and
during spawning behavior/migration (Senthilkumaran, Okuzawa, Gen,
Ookura, & Kagawa, 1999). The Nile tilapia possessing distinguish XY
and XX populations showed sexually dimorphic localization of seabream
GnRH (Swapna et al., 2008). It was documented that three distinct forms
of GnRH in South American cichlid fish were distributed differentially
during sex differentiation (Pandolfi et al., 2002). Similarly, it was re­
ported that GnRHir-neurons were appeared in the POA-H during
gonadal differentiation (Soga, Ogawa, Millar, Sakuma, & Parhar, 2005).
These GnRHir-neurons were found to be increased considerably in the
pejerrey during the sex determination period (Somoza, Miranda, Guil­
gur, & Strobl-Mazzulla, 2006). Whereas in sea bass, during gonadal
differentiation, the GnRH levels reached peak in pituitary and brain
(Moles, Carrillo, Mañanós, Mylonas, & Zanuy, 2007). Infact, it was
suggested by Baroiller et al. (1999) that the HHG axis is required for
complete sex differentiation but not its activation. However, stable
GnRH2 and GnRH3 expressions were observed in black sea bass during
531
Aquaculture and Fisheries 7 (2022) 525–539
sex reversal, indicating independence of these two GnRHs in this
mechanism (Breton, DiMaggio, Sower, & Berlinsky, 2015). It is impor­
tant to understand the monoaminergic axis and its crucial role in regu­
lating the HHG axis to analyse sexual dimorphic GnRH localization, in
turn GnRH-GTH axis (Goos, Senthilkumaran, & Joy, 1999; Peter, Tru­
deau, & Sloley, 1991). In teleosts, catecholamines (CA) and 5-HT are the
monoamines that are the major components of central nervous system
regulating various physiological functions, including reproduction.
The photic signals known to affect the HHG axis primarily through
retina and pineal organ in fishes such as the African cichlid, A. burtoni
and major carp, Catla catla (Grens, Greenwood, & Fernald, 2005;
Moniruzzaman & Maitra, 2012). The two GnRH receptors, type-I and
type-II are abundantly expressed in amacrine and ganglion cells
respectively. The visual information is processed by amacrine cells and
the ganglion cells transmit this processed information to the brain, a
neuromodulator in order to influence GnRH in this process (Grens et al.,
2005; Robison et al., 2001). Exposure of major carp, C. catla to constant
darkness and exogenous melatonin treatment resulted in testicular
maturation during preparatory phase of reproductive cycle (Bhatta­
charya, Chattoraj, & Maitra, 2007). It has been reported in the channel
catfish, I. punctatus that the retinal efferents project towards the supra­
chiasmatic nucleus (SCN) and further to other brain areas and later these
SCN neurons projects to the pituitary (Prasada Rao & Sharma, 1982;
Prasada Rao, Job, & Schreibman, 1983). The pineal cells also express
GnRH receptors in the European sea bass, D. labrax (Servili et al., 2010).
Overall the pineal hormone and melatonin affects dopaminergic system,
GnRH, LH, FSH and gonads (Falcón, Migaud, Muñoz-Cueto, & Carrillo,
2010).
S. Tenugu and B. Senthilkumaran
5.3. 5-HT
The 5-HT neurons have a stimulatory effect in neuroendocrine
function by innervating through POA-H upon GnRH-GTH release (Sen­
thilkumaran & Joy, 1996; Senthilkumaran, Okuzawa, Gen, & Kagawa,
2001; Zohar et al., 2010). 5-HT appeared to be a contributing factor for
sexual dimorphism in brain. This provided clue to authors in order to
produce a predominant female population with the use of
para-chlorophenyl alanine, a 5-HT synthesis blocker during the crucial
window of sex determination/differentiation (Raghuveer, Sudhakumari,
et al., 2011; Tsai, Wang, Chang, & Kao, 2001; Tsai & Wang, 1999). Tph
is a homotetramer allosteric enzyme that catalyzes the rate-limiting step
in 5-HT biosynthesis (Raghuveer, Sudhakumari, et al., 2011; Sudhaku­
mari et al., 2010). In the Nile tilapia, Tph2 which is a brain form of tph,
showed prominent expression during 5, 10, 15 and 20 dph XY tilapia
whereas no expression in 5–20 dph XX tilapia. Additionally, Tph tran­
scripts localized through in situ hybridization was found only in 11 dph
male brain specifically in the regions of telencephalon-preoptic area,
olfactory bulb and olfactory epithelium but not in the female brain of
same age. Tph immunoreactivity positive cells were observed in nucleus
preopticus-periventricularis region of male brain of 12 dph but not in
female brain of same age (Sudhakumari et al., 2010). Due to this, the
dimorphic expression of tph may indicate a role in brain sex differenti­
ation of the Nile tilapia. In the catfish, C. gariepinus, tph expression was
increased in males in comparison to females, 50 and 75 dph indicating
variance expression in brain during early development (Raghuveer,
Sudhakumari, et al., 2011). Increased expression of tph2 was correlated
with elevated levels of 5-HT and 5-HTP in the MT treated male brain
fishes, and on the other hand, pCPA treatment decreased tph2 expression
along with 5-HT and 5-HTP levels in the brain of catfish (Raghuveer,
Sudhakumari, et al., 2011).
5.4. Catecholamines
Catecholamines, unlike 5-HT, exerts inhibitory action by dopamine
(DA) and facilitatory effect through norepinephrine (NE) on GnRH–GTH
synthesis and release (Peter et al., 1991; Senthilkumaran & Joy, 1996).
So far epinephrine with detectable levels during resting phase and
increased levels during pre-spawning and spawning phases in the Asian
stinging catfish, H. fossilis was observed, however no role has been
indicated in terms of GnRH–GTH release (Senthilkumaran & Joy, 1995).
In-depth study on the CAergic system during brain sex development of
both sexes in the catfish, C. batrachus revealed sex-specific changes
whereby the female brain depicted elevated tyrosine hydroxylase (th)
expression levels and high copy number compared to males (Mamta
et al., 2014). Elevated th expression was observed in female brain at 50,
75 and 100 dph compared to that of the male brain of same age wherein
50 dph is considered to be as a critical period for gonadal differentiation
in catfish (Mamta et al., 2014; Raghuveer, Senthilkumaran, et al., 2011).
However, the changes in the levels of DA and NE also showed sexual
dimorphism. Whereas in saddleback wrasse, CAs plays an important role
with the commencement as well as completion of sex reversal (Larson,
Norris, Gordon Grau, & Summers, 2003). Furthermore, EE2 treatment
ensued increased CA levels and elevated th expression and MT treatment
revealed lower CA levels, and th expression irrespective of sex (Mamta
et al., 2014). This indicated 5-HTergic system is prominent in male brain
development, whereas CAergic system dominates in female brain
development thus exhibiting brain sex dimorphism.
5.5. NPY
Neuropeptide Y (NPY) is considered as the most pivotal orexigenic
neuropeptide well expressed in mammals, and it has been reported that
NPY stimulates the food intake in teleost fish as in observed in mammals
(Halford, Cooper, & Dovey, 2004; Kalra et al., 1999; Volkoff et al.,
2005). NPY stimulates the release of GnRH from preoptic-anterior
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Aquaculture and Fisheries 7 (2022) 525–539
hypothalamic and pituitary fragments also upon T and E2 in vivo treat­
ment in goldfish and considered to be one of the mechanisms facilitating
the feedback of these two steroids (Peng, Chang, et al., 1993; Peng,
Trudeau, & Peter, 1993). Increased expression of NPY was evident in the
catfish, C. gariepinus brain and testis, and its expression levels were high
at 100 and 150 dph during brain development in females compared to
males. Predominant expression of NPY was found during the
pre-spawning stage of the female brain compared to other reproductive
stages (Sudhakumari et al., 2017). NPY also stimulates the release of LH
in goldfish through direct action on gonadotroph by stimulating the
GnRH release (Trudeau, 1997). Even in the red seabream, NPY stimu­
lated in vitro release of sbGnRH from POA-H slices during immature,
spawning and recrudescence stages (Senthilkumaran et al., 2001). The
action of GnRH release by NPY is direct as it was not altered by antag­
onists of NA, gamma-aminobutyric acid and 5-HT. Studies revealed that
central injection of NPY caused increased dose-dependent food intake in
cohosalmon, channel catfish and goldfish (De Pedro et al., 2000;
López-Patiño et al., 1999; Narnaware, Peyon, Lin, & Peter, 2000; Sil­
verstein & Plisetskaya, 2000). In another study, pretreatment of T and E2
in the goldfish, induced 2–3 fold increase of NPY mRNA expression
levels in the forebrain (telencephalon/preoptic area) region. Moreover,
T activated NPY synthetic activity in the preoptic area of brain that was
revealed by in situ hybridization (Peng, Gallin, Peter, Blomqvist, &
Larhammar, 1994).
5.6. GDNF
In addition to these factors, glial cell line-derived neurotrophic factor
(GDNF), which is a potent survival factor, is majorly involved in con­
trolling several peripheral and central neurons, including dopaminergic
neurons (Airaksinen, Holm, & Hätinen, 2006). GDNF signals bind to the
GDNF family receptors-α through GPI-anchored receptor, which has a
strong binding affinity over GFRα-1 (Trupp, Raynoschek, Belluardo, &
Ibáñez, 1998). Decreased expression of GFRα-1 was observed upon
treatment with 1-methyl-1,2,3,6-tetrahydropyridine leading to neuro­
degeneration with the correlation of L-3,4-dihydroxyphenylalanine,
catecholamines (CA), DA and NE levels in catfish (Mamta & Senthilku­
maran, 2018).
Overall, despite of these sex dimorphic markers identified in the
brain except 5-HT, which is dominant to shown to induce male popu­
lation with its 5-HT synthesis blocking drug, pCPA, otherwise all the
other neurotransmitters are brain factors and all the brain sex changes
are based on gonadal sex (Tsai, Wang, & Fang, 2001). In this context,
mismatching sex steroids, i.e., E2 to male and MT to female through
osmotic pump delivery in the catfish, C. gariepinus, produced differential
effects on certain brain-related genes (Mamta, Sudhakumari, Kagawa,
Dutta-Gupta & Senthilkumaran, 2020). This include minimal expression
of cyp19a1b, GnRH1, gfrα-1 and th in the brain of MT treated female fish.
On the other hand, increased expression of cyp19a1b, GnRH1, gfrα-1 and
th in the brain of E2 treated male fish (Mamta et al., 2020). However, the
transcripts of some of these brain related genes were normally overex­
pressed in females compared to males (Senthilkumaran et al., 2015)
indicating sex steroid based regulation. Thus, sexually dimporphic
expression of tph was shown for the first time in tilapia wherein exclu­
sive expression of tph is evident 5 to 20 dph male brain but not in female
brain. Furthermore, in catfish such gender specific differences were
subsequently shown in tph, 5-HT and 5-HTP (Raghuveer, Sudhakumari,
et al., 2011; Sudhakumari et al., 2010). Differential expression of brain
related genes so far studied exhibiting sexual dimorphism play promi­
nent role at brain level with response to gonadal differentiation, may
causatively or consequentially responds to gonadal sex (Senthilkumaran
et al., 2015). Changes in these brain related-genes along with CAs and
serum 11-KT, E2, T levels indicate brain-gonadal interactions and their
influence on the GnRH-GTH axis through gonadal recrudescence. Some
of the sex reversal genetic markers so far identified from brain are useful
to understand sex differentiation in addition to the endocrine changes in
S. Tenugu and B. Senthilkumaran
teleost under various conditions including endocrine disruption (Kar,
Sangem, Anusha, & Senthilkumaran, 2021; Rajakumar & Senthilku­
maran, 2020; Tenugu, Pranoty, Mamta, & Senthilkumaran, 2021).
6. Monosex population and strategy of a genetic cross
Teleost, most diverse group of vertebrates has increased globally and
become attractive animal models for extensive investigation related to
sex reversal strategies. In order to overcome certain difficulties exhibi­
ted by fishes, for example, lack of growth after maturation, attaining
sexual maturity at different age, flesh quality deterioration which may
lead to mortality and finally one gender performing better than the
other. Considering these, it is worthwhile to produce monosex pop­
ulations as well as reproductively sterile fish to overcome the hurdles.
Sex reversal is one of the strategies/approaches used to produce mon­
osex populations for several purposes in aquaculture. Due to sexual
plasticity, fishes can be easily manipulated to induce sex reversal during
critical stages by hormonal treatment to understand pubertal and
growth related changes and sex dimorphism (Devlin & Nagahama,
2002). The efficient and standard treatment widely used by farmers is
through dietary administration of MT for 3–4 weeks from 10 dpf to
produce monosex male populations in the Nile tilapia (Baroiller &
D’Cotta, 2001; Baroiller, D’Cotta, & Saillant, 2009). In the Japanese
hirame, P. olivaceus, both low as well as high temperature induced male
monosex population whereas intermittent temperature produced 1:1 sex
ratio (Yamamoto, 1999). Interestingly other methodologies such as ge­
netic cross made applicable to produce monosex population, which was
implied in few species. Initiating with the steroid treatment and com­
bined with hybridization in order to produce sex reversal and sterile fish
Fig. 2. Illustrating the genetic cross and pedigree selection in tilapia.
533
Aquaculture and Fisheries 7 (2022) 525–539
in cyprinids, cichlids and salmonids, the field has emerged very quickly
towards chromosome manipulations, polyploidy and gynogenesis.
In the Nile tilapia, O. niloticus YY male broodstock was produced
genetically on a commercial scale. Initially, fry with mixed population
was treated with E2, to identify XY neofemales progeny, which were
further crossed with XY males to identify YY males. YY males were then
crossed to XY neomales, and further offspring were treated with estro­
gen and then progeny were tested for YY neofemales identification. YY
neofemale and YY male were crossed to generate YY male broodstock
production (Mair, Abucay, Abella, Beardmore, & Skibinski, 1997).
Monosex XY population was generated finally after crossing YY male
with normal XX female. A further selection of different strains within the
broodstock lines were tested through the GMT™ technique (Tuan, Little,
& Mair, 1998; Tuan, Mair, Little, & Beardmore, 1999). This methodol­
ogy was first developed in O. mossambicus for small-scale supermale
production (Pandian & Varadaraj, 1990). Whereas in medaka the
monosex population was produced by using Hd-rR.YHNI strain males
and crossing with the d-rR strain females and further crossing the males
produced in the offspring once again with females of d-rR strain which
ultimately resulted in d-rR.YHNI population of males (Scholz et al.,
2003). In another study of turbot, Scophthalmus maximus treatment with
androgen and crossing of induced classic females (fZW) with neomales
(mZW) produced WW female population (Haffray et al., 2009). Female
monosex population through the genetic cross was also performed in
carp and salmonoids (Cnaani & Levavi-Sivan, 2009; Piferrer, 2001).
However, better survival rates of YY males were demonstrated in yellow
catfish, tilapia and rainbow trout compared to low survival rates in other
species such as medaka and fighting fish (George, Pandian, & Kavum­
purath, 2013). This is a good strategy to develop monosex population
S. Tenugu and B. Senthilkumaran
across species which should be taken into consideration and make major
inputs for research in aquaculture. The pedigree for the production of
monosex population in tilapia through hormonal treatment followed by
genetic cross and progeny selection is depicted in Fig. 2.
7. Conclusion and future perspectives
In both wild and domestic strains of teleost, existence of spontaneous
sex reversed and induced sex reversed individuals have been reported.
In most of the species, E2 and 11-KT considered as the predominant
steroids which are linked in the regulation of sex change. The estab­
lishment of monosex population in mammals is easy as X is bigger than
the Y chromosome whereas in fish no distinguish X and Y chromosomes
are present which is often difficult to distinguish through short gun gene
approach. Inspite of this, genetic cross technique with XY, ZZ population
made it easy to work for inducing sex reversal and this is the best way up
to now to obtain monosex population. By combining both natural and
induced steroid and environmental factors sex reversal had improved in
more advance and used in species such as medaka, tilapia and trout
which is often difficult. With the consideration of diversity and plasticity
different species have varied mechanism to undergo sex-change by
signifying independence evolvement of sex reversal. As reported the
spontaneous and induced sex reversal in teleost understandably
revealed the amazing sexual plasticity exhibited by fishes. The hormonal
treatment warrants to maximize the growth with diverse nutrients also
ensuring the meat quality and enhancing the commercial value of the
edible fish. The technique or by the combination of ploidy induction
provides a scope for the male and female broodstock development,
which helps us to understand the underlying mechanisms in the sex
determination and differentiation process. Studies on spontaneous and
induced sex reversals in fish provides a clue for better understanding the
amazing diversity exhibited by fish as well as vertebrate sex determi­
nation. However, the steroid hormones, environmental conditions
stimulating specific sex bias and genes have an independent parallel
differentiating effect which can interrelate to each other but often syn­
ergistically leads to sex differences in the brain. Future work in combi­
nation with economical relevance on sex reversal strategy ensure
development of monosex population for aquaculture benefits. Further­
more, understanding sex reversal in multiple fish species at the molec­
ular level may provide new gene markers to distinguish endocrine
disruption at all levels.
Conflict of interest
The authors declare no conflict of interest concerning to the research
report in the manuscript.
Acknowledgements
The research work mentioned in this review was supported by grant-
in-aid (Ref. No. EMR/2017/000718) from the Science and Engineering
Research Board, India to BS. ST is thankful to Senior Research Fellow­
ship support by Council of Scientific and Industrial Research (Ref. No.
09/414(1150)/2017-EMR-I), India. Authors acknowledge BUILDER
Grant from DBT (Ref. No. BUILDER-DBT-BT/INF/22/SP41176/2020),
India to School of Life Sciences, University of Hyderabad.
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