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Maternal Thyroid and Glucocorticoid Hormone
Interactions in Larval Fish Development, and Their
Applications in Aquaculture
Christopher L. Browna, Elisabeth Criscuolo Urbinatib, Weimin Zhangc, Shannon B. Brownd &
Michelle McComb-Kobzae

a Aquaculture and Enhancement Division, NOAA, NEFSC, Milford, Connecticut, USA
b Centro de Aquicultura, Universidade Estadual Paulista (CAUNESP), Jaboticabal, Sao Paulo,
Brazil
c Institute of Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University,
Guangzhou, PR China
d Department of Biological Engineering, University of Florida, Gainesville, Florida, USA
e Teens4Oceans, Boulder, Colorado, USA
Published online: 27 Jun 2014.

To cite this article: Christopher L. Brown, Elisabeth Criscuolo Urbinati, Weimin Zhang, Shannon B. Brown & Michelle McComb-
Kobza (2014) Maternal Thyroid and Glucocorticoid Hormone Interactions in Larval Fish Development, and Their Applications in
Aquaculture, Reviews in Fisheries Science & Aquaculture, 22:3, 207-220, DOI: 10.1080/23308249.2014.918086

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Maternal Thyroid and Glucocorticoid
Hormone Interactions in Larval Fish
Development, and Their Applications
in Aquaculture

CHRISTOPHER L. BROWN,1 ELISABETH CRISCUOLO URBINATI,2 WEIMIN ZHANG,3

SHANNON B. BROWN,4 and MICHELLEMcCOMB-KOBZA5

1Aquaculture and Enhancement Division, NOAA, NEFSC, Milford, Connecticut, USA
2Centro de Aquicultura, Universidade Estadual Paulista (CAUNESP), Jaboticabal, Sao Paulo, Brazil
3Institute of Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, PR China
4Department of Biological Engineering, University of Florida, Gainesville, Florida, USA
5Teens4Oceans, Boulder, Colorado, USA

Thyroid hormones (THs) have long been known to have regulatory roles in the differentiation and maturation of vertebrate

embryos, beginning with the knowledge that hormones of maternal origin are essential for human fetal central nervous

and respiratory system development. Precise measurements of circulating THs led to insights into their critically important

actions throughout vertebrate growth and development, initially with amphibian metamorphosis and including

embryogenesis in fishes. Thyroid cues for larval fish differentiation are enhanced by glucocorticoid hormones, which

promote deiodinase activity and thereby increase the generation of triiodothyronine (T3) from the less bioactive thyroxin

(T4). Glucocorticoids also induce the expression of thyroid hormone receptors in some vertebrates. Maternally derived

thyroid hormones and cortisol are deposited in fish egg yolk and accelerate larval organ system differentiation until larvae

become capable of endogenous endocrine function. Increases in the T3/T4 ratio during larval development may reflect the

regulatory importance of maternal thyroid hormones. Experimental applications of individual hormones have produced

mixed results, but treatments with combinations of thyroid and corticoid hormones consistently promote larval fish

development and improve survival rates. The developmental and survival benefits of maternal endocrine provisioning are

increased in viviparous fishes, in which maternal/larval chemical contact is prolonged. Treatments with exogenous thyroid

and corticoid hormones consistently promote development and reduce mortality rates in larval fishes, with potential

hatchery-scale applications in aquaculture.

Keywords thyroid, larvae, embryo, maternal, cortisol

INTRODUCTION

Thyroid hormones (THs) are recognized not only as the

main determinant of metabolic rate in homeotherms, but also

as primary signals for the regulation of diverse growth and

developmental and maturational processes throughout the

vertebrates. Our initial understanding of the actions of THs

was based almost entirely on human pathology and physiol-

ogy, and the familiar and devastating pathological effects of

acute thyroid deficiencies in cases of goiter and cretinism. A

comparative perspective emerged with the technology for pre-

cise quantification of circulating hormones, and critically

important morphogenic roles of THs among the vertebrates

became apparent. These morphogenic actions evolved in fishes

and they are essential to successful embryogenesis.

The first clear link between thyroid function and meta-

morphosis was reported by Gudernatsch (1912), who

described a simple bioassay in which feeding various

� Christopher L. Brown, Elisabeth Criscuolo Urbinati, Weimin Zhang,

Shannon B. Brown, and Michelle McComb-Kobza

Address correspondence to Christopher L. Brown, Aquaculture and

Enhancement Division, NOAA, NEFSC, 212 Rogers Avenue, Milford, CT

06460, USA. E-mail: Christopher.L.Brown@noaa.gov

Reviews in Fisheries Science & Aquaculture, 22:207–220, 2014
Published with license by Taylor & Francis
ISSN: 2330-8249 print / 2330-8257 online
DOI: 10.1080/23308249.2014.918086

207

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mammalian thyroid gland tissues to Rana sp. tadpoles pro-

duced “extremely small (pigmy-) frogs.” Thyroid-dependent

developmental actions extend well beyond the regulation of

amphibian metamorphosis and a role in cretinism, and most

morphogenic actions of thyroid hormones are far less dra-

matic than Gudernatch’s (1912) “maturational” effects.

Milder transitions, e.g., larval metamorphoses among a

majority of fishes, are also controlled by THs (reviewed by

Power et al., 2001), as are a range of developmental and

growth effects among vertebrates. The maturational actions

of THs include the promotion of growth and development

by way of hypertrophy and hyperplasia as well as the reor-

ganization of tissues resulting in differentiation. Many of

the actions of THs are closely associated with reproduction

and embroygenesis.

Serious risks to the offspring of hypothyroid mothers are

recognized, and hormone replacement treatment is custom-

ary (Lebeau and Mandel, 2006). The human maternal endo-

crine contribution is viewed as “critical for proper in utero

brain development” (Howedshell, 2002). Routine screening

of pregnant human subjects for adequate thyroid function

began in the early 1970s (Dussault, 1999). Maternal thyroid

activity is enhanced during human embryogenesis, partly in

response to a thyrotropic action of Human Chorionic

Gonadotropin (HCG) during pregnancy (Fantz et al., 1999).

Human fetal central nervous system (CNS; Haddow et al.,

1999) and respiratory tract (e.g., see Rajatapiti et al., 2005)

differentiation are among processes in human development

that are directly dependent on maternal thyroid contribu-

tions. Thyroid hormone receptors (THRs) enable early

human embryos to respond to maternal thyroid hormones

before fetal thyroid hormone production has begun (Patel

et al., 2011). Incidental elevations of circulating maternal

THs in pregnant sheep result in changes of the texture and

color of wool in the resultant lambs (Kenyon et al., 2004).

Elevated maternal circulating levels of thyroxin (T4) during

human pregnancy provide vital support to healthy human

embryo differentiation before endogenous fetal hormone

production begins, and a suite of placental deiodinases

ensures fetal provision of essential THs by even mildly

hypothyroidal mothers, as well as protection of the fetus

against exposure to excessive quantities (Burrow et al.,

1994). The practice of clinical hormone replacement therapy

for premature infants also underscores the early develop-

mental importance of maternal endocrine contributions. The

effectiveness of treatment of premature infants with T4 or

triiodothyronine (T3) alone was challenged by various

investigators who noted that thyroid hormone applications

did not consistently improve survival or correct problems

associated with respiratory distress syndrome (see Osborn,

2001; Farwell, 2008). This may have been at least partly a

result of the absence of permissive actions imparted by glu-

cocorticoids; the combined effectiveness of thyroid and cor-

ticoid hormones administered together is well established

(Smith and Sabry, 1983). This combination of treatments is

routinely used to promote lung maturation and surfactant

production in preterm babies (see Ballard, 1980).

THYROID HORMONE SYNERGISM WITH CORTISOL
IN FISH DEVELOPMENT

A possible significance of THs in early fish growth and

development was implied by the acute responsiveness of very

young fish to antithyroid drugs and hormone supplementation

treatments (reviewed by Youson, 1988; Brown and Bern,

1989; Dickhoff et al., 1990). The sensitivity of newly hatched

fish to THs was reported by Lam and others who found that T4

treatment accelerated development and larval metamorphosis,

and increased survival rates (Lam, 1980; Lam, 1985; Lam and

Sharma, 1985). Also, in a role similar in many ways to the

endocrine regulation of anuran metamorphosis, thyroid signals

initiate some developmental changes later than the larval-to-

juvenile metamorphosis, such as the transition of upright-

swimming larval flatfishes into asymmetrical juveniles begin-

ning after the completion of yolk absorption (Tagawa et al.,

1991; Inui et al., 1994). By the time of metamorphosis in flat-

fishes, maternal hormones stored in yolk have been fully

depleted and the larval pituitary/thyroid axis has attained func-

tionality (De Jesus et al., 1991). Metamorphic climax among

the flatfishes bears strong similarities to the events seen in

amphibian metamorphosis (see Miwa et al., 1988; Tagawa

et al., 1991). The regulation of smolting in salmonids is also

controlled in part by thyroid system signals (see Robertson,

1949; Miwa and Inui, 1985). Early perceptions of the role of

THs in development have been confounded by a history of

contradictory reactions to exogenous thyroid compounds;

some cases of aberrant development are associated with higher

hormone doses (see Table 1) and other negative responses

remain unexplained.

Physiological effects of cortisol on thyroid-mediated pro-

cesses in fishes are more than additive, or synergistic (Ban,

2005). A synergistic action of cortisol and THs has been iden-

tified in flatfish metamorphosis (De Jesus et al., 1990; De

Jesus et al., 1991), and a close interaction of the two endocrine

systems is also seen in the promotion of amphibian metamor-

phosis (Krug et al., 1983). An emerging view of glucocorti-

coid signaling is that it not only enables important vertebrate

organ systems to respond to THs through synergistic actions,

as in amphibians, but that surging glucocorticoid secretions

facilitate major transitions within a life cycle, serving a prepa-

ratory and synchronizing role in organisms approaching a

major change to the next life history stage (Wada, 2008).

In some cases, cortisol treatment results in increases in thy-

roid hormone activity by increasing the generation of T3

(Redding et al., 1991). Thyroxin is generally viewed as a thy-

roid system prohormone (K€uhn et al., 1994), in which thyroid-

mediated endocrine activity is determined largely by the action

of peripheral deiodinase enzymes. Peripheral outer ring deio-

dination converts T4 into 3,5,3’-triiodothyronine, or T3, which

208 C. L. BROWN ET AL.

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is an order of magnitude more biologically potent than T4

(Orozco and Valverde, 2005). Cortisol promotes the conver-

sion of T4 into T3 by activating outer ring deiodinase activity

(Vijayan et al., 1988; Arjona et al., 2011), and increasing the

T3/T4 ratio is one mechanism by which cortisol promotes thy-

roid-mediated processes. Ontogenetic patterns in developing

fishes that reflect this relationship can be seen in the golden

sea bream, Sparus aurata; increasing cortisol levels are

accompanied by a sharp increase in the ratio of T3/T4 late in

larval development, resulting in significant physiological and

morphological changes (Szisch et al., 2005). Concurrent ele-

vations of T3, T4 and cortisol also precede the larval-to-juve-

nile transition in the silver sea bream, S. sarba (Deane and

Woo, 2003). Whole body cortisol content increases as

Table 1 Effects of treatment with exogenous thyroid hormones on embryonic/larval fish development

Species Hormone treatment, dose actions reported Authors

Chum Salmon Immersion T4, 0.08–0.4 ppm Dales and Hoar, 1954

(Oncorhynchus keta) Accelerated but disproportionate growth and pigmentation

Chum Salmon Immersion T4, 1 ppm Honma and Murakawa, 1955

(Oncorhynchus keta) Reduced weight, physical deformities

Chum Salmon Immersion T4, 0.08 ppm Ali, 1961

(Oncorhynchus keta) Early hatch

Brown trout Immersion T4, 1.0–10 ppm Woodhead, 1966

(Salmo trutta) Rapid differentiation, morphological abnormalities

Mozambique tilapia Immersion T4, 0.1 ppm Lam, 1980

(Sarotherodon mossambicus) Accelerated development and *% survival

Mozambique tilapia Immersion T4, 0.1–0.5 ppm Nacario, 1983

(Sarotherodon mossambicus) Accelerated growth, *% deformities at higher T4 doses

Olive flounder Immersion T4, 0.01–0.1 ppm Inui and Miwa, 1985

(Paralichthys olivaceus) Induced metamorphosis Miwa and Inui, 1987

Common carp Immersion T4, 0.01, 0.05, 0.1 ppm Lam and Sharma,1985

(Cyprinus carpio) Improved hatch rate, *% survival

Milkfish Immersion T4, 0.5 ppm Lam et al., 1985

(Chanos chanos) Accelerated development

Guppy Immersion T4, 0.5 ppm Lam and Loy, 1985

(Poecilia reticulata) Shortened brood interval w/intact offspring

Olive flounder Immersion T4, 0.01–0.1 ppm Miwa and Inui, 1987

(Paralichthys olivaceus) Induced metamorphosis

Striped bass Maternal injection T3 20 mg/gbw Brown et al., 1988a,b

(Morone saxatilis) Improved growth, *% swimbladder inflation, *% survival

Goldfish Immersion T3, 0.01–0.02 ppm, T4, 0.01–0.1 ppm Reddy and Lam, 1992a

(Carassius auratus) Faster fin differentiation, growth and development

Mozambique tilapia Immersion T3, 0.01 ppm, T4, 0.05 ppm Reddy and Lam, 1992b

(Oreochromis mossambicus) Fin differentiation, deformities at highest dose

Rabbitfish Maternal T4 injection, 1,10,100 mg/gbw Ayson and Lam, 1993

(Siganus guttatus) Improved growth, *% survival

Brown trout Maternal T3 injection, 20 mg/kg Mylonas et al., 1994

(Salmo trutta) *% skeletal abnormalities

Striped bass Immersion T3, 0.05–0.1 ppm Huang et al., 1996

(Morone saxatilis) At higher dose: + growth, +% survival

Zebrafish Immersion T3, 5 nM (.003 ppm) T4 30 nM (.02 ppm) Brown, 1997

(Danio rerio) Accelerated fin development

Amberjack Maternal injection T3, 20 mg/kgbw Tachihara et al., 1997

(Seriola lalandi) Survival more than doubled

Korean rockfish Maternal injection T3, 20 mg/kgbw Kang and Chang, 2004

(Sebastes schlegeli) Increased growth, *% survival

Goldfish Feeding T3, 1.25–6.25 ppm Swain and Sahoo, 2003

(Carassius auratus) Increased growth, disease resistance

Piracanjuba Immersion T3, 0.01, 05, 0.1, 0.5,1 ppm, Landines et al., 2010

(Brycon orbignyanus) *% survival-reduced cannibalism

Zebrafish Immersion T3, 5 nM D .003 ppm Walpita et al., 2007

(Danio rerio) Accelerated pigmentation and *% hatching

Matrinx~a Maternal injection T3, 10–20 mg/kg Urbinati et al., 2008

(Brycon amazonicus) Immersion, 0, 0.01, 0.05, 0.1 mg/L

Improved growth, +% abnormalities

Nile tilapia Maternal injection T4, 1 or 10 mg/g Khalil et al., 2011

(Oreochromis niloticus) Increased growth, rapid development, *% survival

Reviews in Fisheries Science & Aquaculture vol. 22 no. 3 2014

MATERNAL THYROID AND GLUCOCORTICOID HORMONE INTERACTIONS IN LARVAL FISH 209

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numerous species of larval fishes approach the transition into

juvenile forms, possibly to coordinate various events (Wada,

2008), in some cases by synergizing with thyroid hormones

(Hwang et al., 1992; Tanaka et al., 1995). Sudden increases in

T3/T4 ratios coincident with transitions from the larval to juve-

nile stage have been observed (e.g., see Nayak et al., 2001;

McComb et al., 2005), which may or may not reflect glucocor-

ticoid synergism in thyroid-driven developmental actions.

The acute responsiveness of very young larval fishes to THs

seemed paradoxical or artifactual for a number of years, since

those cases often revealed hormone-sensitivity in animals that

had not yet developed functional pituitary/thyroid axes

(Mommsen and Walsh, 1988). Hormone radioimmunoassays

of yolk extracts revealed the presence of ample amounts of T4

and T3 in unfertilized fish eggs (Kobuke et al., 1987; Brown

et al., 1987; Tagawa and Hirano, 1987). Maternal deposition

of hormones in yolk raises the possibility of maternal/larval

endocrine communication in early development in oviparous

fishes (Mommsen and Walsh, 1988). Thyroid hormones of

maternal origin have been found in unfertilized eggs consis-

tently among oviparous vertebrates, suggesting maternal pro-

visioning and a mechanism of delivering regulatory signals to

developing embryos long before the onset of endogenous thy-

roid competence. Circulating THs in pre-spawning female rab-

bitfish (Siganus guttatus) accumulate in oocytes during

vitellogenesis, resulting in improved larval performance and

survival (Ayson and Lam, 1993). Developmental research

using zebrafish (Danio rerio) as a model confirms thyroid

stimulation of various processes of fin, scale, and pigment dif-

ferentiation in this species (Brown, 1997). Goldfish respond in

similar ways to exogenous THs, with improvements in fin,

skin, and scale development, growth, and resistance to chal-

lenges with pathogens (Reddy and Lam, 1992a; Shinobu and

Mugiya, 1995; Swain and Sahoo, 2003). Other maternal hor-

mones, especially small steroid molecules such as cortisol are

also found in the yolk of unfertilized fish eggs (reviewed by

Tagawa, 1996; Brooks et al., 1997) and may be necessary for

permissive or other effects. Interactive and sometimes syner-

gistic effects of thyroid and corticoid hormones in larval fish

development (Table 2) are consistent with the concept of com-

binations of maternal signals interacting to coordinate and pro-

mote developmental processes in young fishes, increasing the

likelihood of larval survival. Maternally derived cortisol and

testosterone deposited in yolk interact in the regulation of

growth and development in larval damselfishes (McCormick,

1999). Combined treatments with supplemental TH and corti-

sol consistently accelerate digestive system ontogeny (Kim

and Brown, 2000; Nayak et al., 2000a) and swimbladder func-

tion, resulting in reduced rates of mortality of larval fishes

(Kim and Brown, 1997; Sri Prudi et al., 2002; Nayak et al.,

2003).

Extensive evidence implicates THs in the regulation of var-

ious aspects of growth (see reviews by Donaldson et al., 1979;

Power et al., 2001). A majority of the studies mentioned above

indicate that exogenous THs stimulate or accelerate

development and result in enhanced survival in larval fishes.

Some species are unresponsive or have very limited responses

to alterations of thyroid hormone levels alone (Tagawa and

Hirano, 1990; Witt et al., 2009) or show detrimental effects of

exogenous THs (see Table 1; Higgs et al., 1982; Huang et al.,

1996). Hormone interactions (e.g., low levels of permissive

compounds), species differences and dose-dependency may

account for some inconsistencies in the responses of larvae to

exogenous THs. Among species differences, untoward effects

of exogenous THs are often seen in fishes with large eggs,

high survival rates, and presumably ample supplies of mater-

nal THs, such as the salmonids (see Mylonas et al., 1994).

Overstimulation of skin, bone, and scale development by

higher doses of THs in post-larval stages may partially explain

their capacity to induce deformities (Karg, 2007). Some defor-

mities may be caused by the promotion by exogenous hor-

mones that regulate developmental processes when the timing

of exposure or sensitivity is skewed or when ample amounts

of required materials are unavailable (Brown et al., 2010).

Similarly, treatment of larval tilapia with cortisol alone pro-

motes growth and development inconsistently and in a dose-

related fashion (Mathiyalagan et al., 1996). Under some con-

ditions, treatment with exogenous cortisol alone improves the

survivial rate of larval Asian seabass, Latifes calcarifer, by

undetermined mechanisms (Sampath-Kumar et al., 1993).

THE PITUITARY/THYROID AXIS AND MOLECULAR
MECHANISMS IN DEVELOPMENT

The presence of THs and cortisol has been reported in fish

at all developmental stages beginning in unfertilized eggs (see

Brooks et al., 1997; Szisch et al., 2005), and stimulation by

endocrine compounds during embryogenesis and organogene-

sis appears to be of vital importance. Ontogenetic studies of

endocrine functions suggest that the maternal endocrine con-

tributions to offspring sustain fish through the earliest of devel-

opmental stages, beginning with fertilization, before

developing embryos have acquired endocrine competence.

One apparent cascade of actions in oviparious fishes begins

with maternal deposition of cortisol and THs in egg yolk,

resulting in the promotion of deiodinase activity and THR

expression by cortisol, and induction by THs of growth factors

in developing embryos leading to accelerated differentiation.

The central nervous system, digestive tract, skin, fins, and

swimbladder appear to be targets for endocrine stimulation of

development. Although some authors conclude that the physi-

ological significance of maternally derived cortisol in fish

eggs is uncertain, it appears likely that permissive or synergis-

tic actions of corticoids in thyroid-regulated processes may be

of adaptive value (Brooks et al., 1997). Very early contribu-

tions of maternal THs to larval differentiation and survival are

confirmed by the presence of thyroid hormone receptors

(THR) long before endogenous thyroid hormone synthesis

begins; several isoforms are expressed from the very first

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stages of development in zebrafish (Darras et al., 2011). Genes

encoding the TRaA1 thyroid hormone receptor (TR) begin

expression in zebrafish zygotes about 3 hr post-fertilization

(Essner et al., 1997), suggesting that hormone responsiveness

is an urgent embryonic need. The detection of THR long

before the onset of larval thyroid function in zebrafish has led

to some doubt of the physiological role of hormone-receptor

endocrine signaling in early development (Essner et al., 1997;

discussed by Power et al., 2001), but zebrafish embryos have

(Walpita et al., 2007) and are capable of responding to THs of

maternal origin (Darras et al., 2011).

Unfertilized zebrafish eggs contain maternally derived THR

transcripts, followed by early zygotic transcription of TR and

TR mRNA (Liu and Chan, 2002; Walpita et al., 2007). Mater-

nal provisioning of egg yolk in the zebrafish also includes cor-

tisol, and experimental interference with the response of

zebrafish embryos to glucocorticoids leads to reduced growth,

impaired organogenesis, and increases in the rate of mortality

(Nesan, 2013). The possible interdependence of cortisol and

THs in larval fish development is supported by the maternal

provisioning of both groups of hormones in egg yolk and their

synergistic actions when applied together experimentally

(Table 2). Significant cross-talk between interrenal and thy-

roid systems may be characteristic of early teleost develop-

ment, with synergistic promotion by glucocorticoids of the

expression of THR and the stimulation of peripheral deiodi-

nases (De Nayer et al., 1987; Terrien and Prunet, 2013). These

two mechanisms are at least partly responsible for the synergy

of corticosteroids with TH during tadpole metamorphosis

(Bonett et al., 2010).

The evolutionary implications of the sensitivity of larval

fishes to maternal hormones are profound. Subtle effects of

early exposure to maternal hormones on the dynamics of

developmental processes include not only improved survival,

but also altered trajectories of developmental patterns,

with disproportionately large impacts throughout later

developmental stages and substantial evolutionary consequen-

ces (Bernardo, 1996). Beneficial effects of maternal invest-

ment on development and consequently on larval survival

(Brown et al., 1988a,b; Chambers and Legget, 1996) can have

a considerable impact on year-class size through the attain-

ment of reproductive capability (Leggett and Deblois, 1994).

Early thyroid-driven events among teleosts led one group of

authors to conclude that “even a slight change in activity of

the thyroid axis during ontogeny can be the cause of wide mor-

phological variability. . . and may underlie explosive diversifi-

cation of the species” (Shkil et al., 2010, p. 369).

It is not known whether patterns of maternal signaling may

influence behavior in a lasting manner, comparable to the

apparent effects on physiology and morphology, although

some adaptive behavioral effects of maternal cortisol signals

to young fishes and other vertebrates have been described.

Female sticklebacks (Gasterosteus aculeatus) responded to

pre-spawning exposure to simulated threats of predation by

producing enlarged eggs with elevated cortisol content (Geis-

ing et al., 2010). Enlarged, cortisol-enriched eggs produced

fry that showed potentially adaptive physiological and behav-

ioral effects, interpreted by these authors as a maternal signal

imparting improved fitness to fry by pre-adapting offspring

to a sub-optimal environment (Geising et al., 2010). Expo-

sure of gravid damselfish, Pomacentrus amboinensis, to com-

petitors or predators caused elevations in plasma cortisol,

with potentially adaptive influences on larval size and quality

(McCormick, 1998). Maternal stress in an oviparous lizard,

Lactera vivipara, increases the corticosteroid content of

eggs. Experimental increases of egg content of corticosterone

in this species result in altered, apparently adaptive patterns

of predator-avoidance behavior in the resultant offspring

(Uller and Olsson, 2006).

Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) are

mitogenic factors, which play important roles in growth and

development in vertebrates (Jones and Clemmons, 1995)

Table 2 Effects of combined thyroid hormone (T3 or T4)/cortisol (F) treatment on larval fish development

Hormones, dose species Actions reported Authors

Japanese flounder T3 or T4 0.001–1.0 C F 0.1 ppm De Jesus et al., 1990

(Paralichthys olivaceus) Earlier fin ray resorption

Pacific threadfin, or moi T3 2.6 ppmC F 0.1 ppm Brown and Kim, 1995

(Polydactylus sexfilis) Earlier initial gut function

Pacific threadfin, or moi T3 2.6 ppmC F 0.1 ppm Kim and Brown, 1997

(Polydactylus sexfilis) Earlier gut formation, *% survival, + deformities

Pacific threadfin, or moi T3 2.6 ppmC F 0.1 ppm Kim and Brown, 2000

(Polydactylus sexfilis) Enhanced & earlier digestive enzyme expression

Indian carp T4 2.6 ppmC F 0.1 ppm Nayak et al., 2000a

(Catla catla Ham.) Earlier yolk absorption, gut & swimbladder formation

Indian catfish T4 2.6 ppmC F 0.1 ppm Nayak et al., 2000b

(Heteropneustes fossilis) Earlier yolk absorption & gut formation, *% survival

Sand goby T3 2 ppm C F 1 ppm Sri Pudju et al., 2002

(Oxyeleotris marmorata Blkr.) Improved swimbladder formation, *% survival

Indian catfish T4 0.05 ppmC F 0.5 ppm Nayak et al., 2003

(Heteropneustes fossilis) *% hatch, early yolk abs., + deformities, * weight, *% survival

MATERNAL THYROID AND GLUCOCORTICOID HORMONE INTERACTIONS IN LARVAL FISH 211

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including teleosts (Wood et al., 2005). The presence of IGFs

and their receptors has been demonstrated during early devel-

opment of fish (Greene and Chen, 1997, 1999). Although lack-

ing direct evidence at present, there exists a possibility that

some cortisol and thyroid hormone mediated developmental

actions may be transduced by IGF signals, at least partly, to

regulate embryogenesis in teleosts.

Both IGF-1 and IGF-2 are expressed in the unfertilized eggs

and embryos of gilthead seabream (Funkenstein et al., 1996)

and rainbow trout (Greene and Chen, 1997), whereas only

IGF-2 mRNA was detected in rabbitfish unfertilized eggs and

embryos during the cleavage stage, and IGF-1 mRNA was first

detected in the larvae soon after hatching (Ayson et al., 2002).

These results suggest that the roles of IGF-2 in fish embryo-

genesis may be crucial and conserved as in mammals

(Dechiara et al., 1990). Cortisol suppression of IGF-1 expres-

sion seems to be conserved in teleosts, but in hepatocytes of

coho salmon (Pierce et al., 2010) and tilapia (Pierce et al.,

2011) cortisol was shown to up-regulate IGF-2 mRNA levels,

either directly or via enhanced Growth Hormone (GH)

response. In rainbow trout embryos reared from cortisol-

enriched oocytes, however, IGF-1 expression was significantly

enhanced from the zygote to 21-days post-fertilization (dpf)

embryos and IGF-2 was enhanced in the 21-dpf embryos (Li

et al., 2010). These results suggest that the regulation of IGF

expression by cortisol may be different in fish embryos from

that in adults, and cortisol may act via IGF-1 and/or IGF-2

signals to regulate embryogenesis.

Insulin-like growth factors (IGF) expression is promoted by

thyroid hormones in fish. Hepatic IGF-1 mRNA expression

was stimulated either by T3 in tilapia (Schmid et al., 2003)

and zebrafish (Wang and Zhang, 2011) or by T4 in sea bream

(Leung et al., 2008). Tissue remodeling during metamorphosis

in the Atlantic halibut (Hippoglossus hippoglossus) is medi-

ated by endocrine changes involving both THs and IGF-1 (Hil-

dahl et al., 2008). However, the basal and GH-stimulated IGF-

2 expression was suppressed by T3 in salmon hepatocytes

(Pierce et al., 2010). The above studies in fish adults suggested

that hepatic IGF-1 and IGF-2 are inversely and differentially

regulated by cortisol and THs. However, in fish embryos, the

regulation of IGF-1 and IGF-2 by cortisol and particularly by

THs is poorly understood, and worthy of further study.

RELATEDNESS OF THYROID AND REPRODUCTIVE
ENDOCRINE SYSTEMS

The connection between thyroid signaling and embryo

competence does not appear to be coincidental. It has been

suggested that the regulation of reproduction and thyroid func-

tion are evolutionarily intertwined (reviewed by Cyr and

Eales, 1996). Several lines of evidence point to the interrelat-

edness of these two endocrine systems, starting with chemical

and functional similarities in adenohypophysial compounds in

fish. The alpha sub-units of hypophysial glycoproteins

thyrotropin (TSH) and leuteotropic hormone (LH) are identi-

cal, with considerable overlap and systemic interaction in their

actions (see Norris, 2007); both come from histologically

indistinguishable pituitary basophil cells and function by way

of cAMP-dependent second messenger systems. Differing

functional activities among this related family of glycoprotein

hormones are conferred by distinct beta subunits, encoded by

different genes than the shared alpha subunits (Szkudlinski

et al., 2002). Prevailing opinions are that that these regulatory

hormones arose from a series of gene duplications, with con-

siderable conservation of structural and biochemical character-

istics (Wallis, 2010). The elaboration of hypophysial

glycoproteins (TSH, LH, FSH) appears to have begun with an

ancestral hormone in the cyclostomes, probably with gonado-

tropic function (Kawauchi and Sower, 2006).

A consistent functional link has persisted between cyclic

changes in thyroid and gonadal activities in modern fishes.

Although fishes exhibit innumerable reproductive strategies, a

pattern of increased thyroid hormone activity during early to

peak oogenesis is consistently seen among diverse female

fishes (Cyr and Eales, 1996).

Transfer of maternally derived corticoid hormones to fish

eggs reportedly has a mix of beneficial and harmful effects on

embroygenesis. It is possible that adaptive acceleration of

organogenesis contingent on transient endocrine effects

including thyroid/corticoid synergism may give way to damag-

ing effects of relatively higher or more prolonged, dose-depen-

dent maternal signals during longer-term stress. Prolonged

elevations of cortisol in rainbow trout (Oncorhynchus mykiss)

under chronic stress resulted in compromised larval fitness

(Campbell et al., 1992, 1994).

MATERNAL HORMONES IN ELASMOBRANCH
REPRODUCTION, AND THE EVOLUTION
OF VIVIPARITY

The reproductive strategies of elasmobranchs (sharks,

skates, and rays) are subject to tremendous diversity, with ovi-

parity being the most ancestral mode and the one found in all

skates and a minority of sharks. Viviparity is the predominant

mode; live birth is found in 55% of chondrichthyan fishes and

in 70% of shark species (245–270 species). There are 270

viviparous ray species, which include stingrays, guitarfish, elec-

tric rays, and the sawfish. In contrast, only 2–3% of bony fish

are viviparous. Viviparity has evolved from oviparity on as

many as 18 separate occasions (Wourms and Lombardi, 1992).

The evolution of viviparity in elasmobranchs has resulted in

lecithotrophic and matrotrophic modes. Yolksac viviparity

involves retention of eggs inside the female until fully devel-

oped with no maternal chemical contribution beyond yolk.

This is the most widespread mode in elasmobranchs and con-

fers adaptive advantages over the vulnerabilities inherent in

egg deposition. There are matrotrophic modes including histo-

trophy, in which yolk stores are supplemented with maternal

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proteins and lipid-rich histotroph secreted directly from the

uterus, and oophagy in which embryos continually ingest

unfertilized eggs. The most highly derived form of matrotro-

phic viviparity is the placental association in which embryonic

yolksacs eventually become depleted and differentiate into the

fetal portion of placentas, providing direct humoral exchange

with the maternal circulation (Wourms and Demski, 1993).

Prolonged exposure to yolk followed by direct humoral

exchange via placentae enables plasticity in maternal contribu-

tions of development-promoting hormones (Hamlett, 1993).

Progesterone has been identified as a potential driver as it

inhibits myomertrial contractions preventing egg laying while

also inhibiting vitellogenin synthesis necessary for yolk pro-

duction driving placental evolution (Callard et al., 1992). Thy-

roid hormone roles in elasmobranch reproduction and early

development have been studied in a limited number of sharks

and rays. Thyroxin levels have been correlated with reproduc-

tive status in the Atlantic stingray, Dasyatis sabina and the

placental viviparous bonnethead shark, Sphyrna tiburo (Volk-

off et al., 1999; Gash, 2000). Levels of T4 and T3 follow a pat-

tern of variation in the maternal serum and yolk of S. tiburo

during pre-ovulatory, ovulatory, and early gestation stages,

with highest TH levels in serum and yolk occurring concur-

rently during the gravid state nearing implantation. Embryonic

S. tiburo show indications of endogenous TH synthesis later,

as yolk stores approach depletion (McComb et al., 2005). Sig-

nificant increases were seen in T3/T4 ratios later in pregnancy.

It is possible that early endogenous TH synthesis could be sup-

plemented by absorption of maternal TH diffusing into the

yolk as a later component of maternal endocrine provisioning.

Levels of corticosterone were determined in the freshwater

stingray, Potamotrygon cf. histrix (Brinn et al., 2012) and in a

separate study levels of T4, T3, and corticosterone were deter-

mined in the serum and yolk of several freshwater ray species.

A nearly nine-fold increase was found in the glucocorticoid

concentration of uterine fluids that bathed the developing

embryos as compared to yolk and maternal serum levels,

suggesting that these maternal fluids provide a means of con-

tinuous and modulated transfer of development promoting hor-

mones. These fluids also contained T3 and T4 presumably of

maternal origin (M. McComb-Kobza, Teens4Oceans, unpub-

lished data).

Continuous access to maternal endocrine signals imparts

profound developmental and survival advantages. This,

together with prolonged nourishment and physical protection

appears to be a strong suite of drivers behind the repeated evo-

lution of viviparity as a reproductive strategy.

AQUACULTURE APPLICATIONS OF THYROID
AND CORTICOID HORMONES

Increasing recognition of the importance of hormones for

growth and differentiation of embryos was indentified as a

central theme of “the new endocrinology” (Bern, 1990, 1992).

Overlapping roles of hormones and growth factors are criti-

cally important in early embryogenesis, especially with the

knowledge that maternally derived regulatory compounds are

transferred to and stored in yolk and active from the earliest

stages of development (de Pablo and Roth, 1990). Maternal

compounds are supplemented by de novo embryonic mRNAs

beginning in extremely early developmental stages, possibly

directing tissue remodeling and differentiation processes as

paracrine/autocrine factors (Sanders and Harvey, 2008).

Aquaculture management is an effort to optimize aquatic

animal development, growth, survival, and reproduction under

artificial conditions. Aquaculture as a production system has

inherent biological advantages and disadvantages in compari-

son with wild fisheries; hatchery production often imposes

artificially high densities and simplified nutrition parameters

to which some species respond more favorably than others.

The agrarian approach to fish relies on enhanced survival and

accelerated growth, as compared with the survival of an

orders-of-magnitude smaller percentage of wild fishes to

reproductive age. Nutrition can be controlled and predation

and environmental contamination can be regulated or elimi-

nated in aquaculture settings. The reproductive strategy of the

culture subject is a major source of variation in the selection

and development of culture methods. Freshwater fishes gener-

ally produce larger eggs with a higher probability of hatching

and survival (by about tenfold; Rao, 2003). Among marine

species that produce large numbers of tiny pelagic eggs, with

smaller yolk reserves and less maternal investment per indi-

vidual egg (often described as r-selected) the larvae are conse-

quently small and fragile and rearing them in the hatchery is

technically challenging. Most of the species exhibiting

increased survival in response to exogenous hormones fit in

this category and could be characterized as pelagic spawners

that produce large numbers of small, delicate larvae that would

normally be subject to high rates of mortality. It is noteworthy

that early feeding is among the most problematic of larval

rearing issues among these fishes, and that the GI tract, fins,

and swimbladder are repeatedly observed to be among targets

of exogenous TH (see Tables 1 and 2). Demersal spawning

involves a smaller number of larger eggs, and with a higher

probability of survival—a reproductive strategy that has been

viewed as a preliminary form of parental care (Duarte and

Alcaraz, 1989).

The substitution of formulated feeds for natural diets can

have endocrine consequences; e.g., Atlantic halibut (Hippo-

glossus hippoglossus) larvae fed Artemia have a hypothyroid

status compared with larvae that eat wild zooplankton;

Artemia has relatively poorer iodine content, resulting in ele-

vated frequencies of incomplete and problematic halibut meta-

morphoses (Solbakken et al., 2002). Artemia enriched with

iodine impart thyroid-mediated advantages to developing fish

(Hawkyard et al., 2011). Further complicating the endocrine

implications of aquaculture feeds is the confirmation that Arte-

mia synthesize and store both T4 and T3 (see Hawkyard et al.,

2011). Fishmeal-based aquaculture diets also contain T4,

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among other hormones (Feist and Schreck, 1990). Dietary

ingestion of T4—including the consumption of Artemia—can

induce negative feedback, leading to reduced TSH secretion,

resulting in both reduced thyroid hormone production and

decreased deiodination of T4 into T3 (Conti et al., 1978).

The use of thyroid and glucocorticoid hormones to promote

survival in larval fishes for food production is subject to strin-

gent and somewhat complicated regulation in the USA; both

Food and Drug Administration (FDA) approval and Environ-

mental Protection Agency (EPA) compliance are required

(Johnson and Bosworth, 2012). Hormone use in food produc-

tion arouses popular concerns, in part because hormone appli-

cations are popularly associated with patterns of misuse and

with anabolic and secondary sex disfigurement. Public percep-

tions of hormone use in the food industry are often poorly dis-

tinguished from heavy and at times abusive antibiotic and

steroid use in the meat industries, or with the production of

genetically modified organisms. Because consumer-oriented

publications strongly encourage the public to avoid meat prod-

ucts of animals exposed to antibiotics, negative associations

with hormone use have accelerated (e.g., see Bohne and Hal-

loran, 2012). The Food and Agriculture Organization of the

United Nations concludes that the general public’s acceptance

of aquaculture products is affected by perceptions of chemical

hazards that can be far out of proportion to real health or

environmental risks (FAO, 1997).

In addition to a resistance by popular opinion, chemical use

by aquaculture farms is also under stringent governmental reg-

ulation because, relative to meat industries, it is a relatively

new practice and the potential for contamination of surround-

ing bodies of water is more significant (FAO, 1997). Producers

must closely monitor hormone levels in fish and the surround-

ing environment in order comply with United States regula-

tions, but this can be particularly challenging for imported

aquaculture products, or for domestic producers that lack the

means to do the requisite testing (FAO, 1997).

A typical approach of fish culturists wishing to use endo-

crine methods to reduce mortality in larviculture in the USA is

to seek a limited-term exception, an Investigational New Ani-

mal Drug or INAD exemption. Direct applications of hor-

mones in food production are prohibited, even though the

chance of residual thyroid hormones from larval treatments is

negligible. Thyroid hormones deposited in egg yolk disappear

as yolk is consumed, and before endogenous production begins

(e.g., see Greenblatt et al., 1989). Exogenously applied THs

are metabolized shortly after hatching (e.g., see Tachihara

et al., 1997). Material Safety Data Sheet (MSDS) hazard rat-

ings are lower for Thyroxin, rated at zero for each of the four

hazard categories, than those published for Vitamin C, for

which two numerically-ranked categories of hazards are listed.

Some aquaculture-related efforts have been made to

enhance maternal hormone synthesis and transfer of develop-

ment-promoting hormones by environmental and dietary

manipulations to promote endogenous production, with

encouraging results (see Witt, 2008; Witt et al., 2009). A more

direct approach is the maternal injection of exogenous hor-

mones; a cost-effective method that is favored where it can be

used because a single, simple procedure can improve the egg

quality of an entire cohort (Tagawa, 1996). For practical rea-

sons, many advances involving applications of TH in larval

fish culture have occurred in countries other than the United

States. In Japan, maternal T3 injections increased the survival

of larval amberjack, Seriola ialandi, by four-fold, with produc-

tion-scale application in an aquaculture center (Tachihara

et al., 1997). Maternal T3 injections of the viviparous Korean

rockfish Sebastes schlegeli, improved growth and survival suf-

ficiently to provide “a distinct advantage on the enhancement

of seedling productivity. . .” (Kang and Chang, 2004, p. 652).

The larval development of numerous cultured fish species has

been accelerated or improved by thyroid hormone supplemen-

tation (reviewed by Tagawa, 1996; see Table 1), and many of

the beneficial effects can be seen in desirable but difficult-to-

culture marine species that produce small eggs and altricial

larvae.

The larvae of several freshwater fishes of South America

with strong aquaculture potential have also responded favor-

ably to experimental thyroid supplementation, including the

pintado, Pseudoplatystoma coruscans and the dourado Salmi-

nus maxillosus (Landines Parra, 2003), the matrinx~a, Brycon
amazonicus (Urbinati et al., 2008; Leonardo et al., 2013), and

the piracanjuba, Brycon orbigyanus (Landines et al., 2010).

The matrinx~a, Brycon amazonicus, and the piracanjuba,

Brycon orbigyanus, are omnivorous fishes that present low

survival rates and intense cannibalism during the earlier stages

of development in captivity (Senhorini et al., 1998). Supple-

mentation of T3 was tested in both species either by maternal

injection or egg immersion. A study comparing the larval per-

formance of matrinx~a after maternal T3 injection or egg

immersion of T3 showed that both routes of T3 administration

stimulated the early growth of larvae of this species, but earlier

effects were documented when broodstock females were

injected. Larvae from T3-injected females had increased length

after hatching and higher weight from 24 h after hatching,

while the length of larvae produced from T3-immersed eggs

exceeded the control values from 6 days and weight from

8 days (Urbinati et al., 2008). More recently, Leonardo et al.

(2013) demonstrated that newly-hatched larvae were signifi-

cantly heavier when eggs were immersed in T3 and this effect

persisted until 12 days post-hatch when larvae were trans-

ferred to earthen tanks in the routine of the farming of this

fish. Larval survival increased following the hormone treat-

ments, from 26.5% in the control group to approximately 40%

in groups treated with T3. Cannibalism was not affected by the

treatments. The higher weight of T3-supplemented larvae at

hatching may have contributed to the improvement in the sur-

vival rate. Previously, Urbinati et al. (2003) showed that

maternally administered T3 significantly improved the survival

of matrinx~a, probably as a result of reduced cannibalism.

Treated larvae grew more than control specimens up to 6 days

post-hatch and had similar weight at 9 days but at 12–18 days

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the control group showed higher growth compared to the

treated group. Heterogeneous growth in control larvae may

have resulted in an increase in the rate of cannibalism, which

accelerates growth and could account for the lower survival

rate (21.8%) compared with the hormone-treated group

(61.6%).

Triiodothyronine (T3) has also been demonstrated to pro-

mote organogenesis in developing matrinx~a as seen in acceler-

ated muscle hypertrophy in larvae developing from eggs

exposed to the hormone. Those larvae presented larger trans-

verse section area of the muscle fibers than untreated control

larvae at 54 hr after hatching (Vasques, 2003). Moreover, T3

also promoted the development of components of the larval

digestive system. Larvae from T3-treated groups showed the

digestive lumen partially at 18 hr after hatching and, at 30 hr,

it was observed that the mucus layers of the stomachs of

treated larvae were more highly organized than those of con-

trol larvae. At 54 hr, in treated larvae the number of vilosities

in the mucus layer was higher than those of the control larvae,

and they also presented vacuolus cells among those forming

the stomach mucus layer. Only liver tissue of larvae from the

T3 treatments had cells organized in parallel strings.

The supplementation of the matrinx~a larvae diet with tyro-

sine, precursor for the biosynthesis of THs, also showed posi-

tive results in the early larval development of this species

(Hoshiba, 2007). Dietary tyrosine enrichment (5.39 g/100 g

diet—2.4 times the amount of the commercial diet) promoted

higher growth in terms of both weight and length, reduced can-

nibalism and enhanced larval survival.

In the piracanjuba, which has recently been listed as an

endangered species (Fundaç~ao Biodiversitas, 2003), T3

increased the survival to 15 days (Landines et al., 2010), with-

out affecting growth rate. In another study (Dr. Leonardo and

E. Urbinati, Universidade Estadual Paulista, personal commu-

nication), T3 immersion quadrupled the hatch rate compared

with controls (to 858,890 from 204,020 respectively) and hor-

mone-supplementation also produced significant increases in

larval length and weight.

Thirty six hours after hatching larvae were transferred to

aquaria and monitored up to the 9th day of rearing. The weight

and length difference remained along the rearing period and

survival was similar among larvae from all treatments. Two

carnivorous fish species were also investigated in the same lab-

oratory, the dourado, Salminus maxillosus, and the pintado,

Pseudoplatystoma coruscans (Landines Parra, 2003). In both

species, fertilized eggs immersed in T3 solutions did not show

significant changes in larval growth, but had dramatic

improvements in rates of survival (21% for dourado and 23%

for pintado).

CONCLUDING REMARKS

Maternal TH supplementation alone or in combination with

cortisol can confer distinct developmental advantages to

larvae, and has the potential to dramatically enhance fingerling

survival and hatchery production rates (Tables 1 and 2). This

appears to reflect an evolutionary mechanism in which mater-

nally derived endocrine signals stimulate embryogenesis and

thereby convey survival value through the critical time of first-

feeding, and it has potential applicability as a means of

improving production in the mass culture of fishes with large

numbers of small, delicate larvae. Perceived and perhaps legit-

imate hazards of thyroid and glucocorticoid hormone applica-

tions in aquaculture are the subject of legal and public opinion

based concerns.

ACKNOWLEDGMENTS

Sincere thanks are expressed to Dr. Masatomo Tagawa at

Kyoto University and to Emeritus Professor Lam at the

National University of Singapore for their thoughtful and con-

structive reviews of this manuscript.

FUNDING

This work was partly supported by the Special Fund for Agro-

scientific Research in the Public Interest (201403008) of the

People’s Republic of China.

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