Journal of Ethnopharmacology 121 (2009) 229–233

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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Morinda citrifolia Linn (Noni): In vivo and in vitro reproductive toxicology

Juliane C. Müller, Giuliana G.K. Botelho, Aedra C. Bufalo, Ana C. Boareto, Yanna D. Rattmann,
Elisangela S. Martins, Daniela A. Cabrini, Michel F. Otuki, Paulo R. Dalsenter ∗
Department of Pharmacology, Federal University of Paraná, P.O. Box 19031, CEP 81531-990 Curitiba, PR, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Morinda citrifolia Linn (syn. Noni) is a plant widely used as food and medicine worldwide but there are no
Received 27 March 2008 toxicological tests about this plant focused on reproduction.
Received in revised form 10 October 2008 Aim of the study: To investigate possible endocrine activity and toxic effect on the reproductive system of
Accepted 18 October 2008
Wistar rats by exposure of aqueous extract of the Morinda citrifolia.
Available online 30 October 2008
Materials and methods: Two experimental protocols in vivo were developed, (a) uterotrophic assay and (b)
in utero and lactational assay, and one test in vitro to investigate the effect on the contractility of pregnant
Keywords:
uteri isolated from rats (doses of the extract: 7.5, 75 and 750 mg/kg).
Morinda citrifolia Linn
Reproductive toxicology
Results: The uterotrophic assay indicates presence of in vivo antiestrogenic activity of extract at doses of
Antiestrogenic activity 7.5 and 750 mg/kg. The in utero and lactation exposure showed that the treatment with extract at the dose
Rubiaceae of 7.5 mg/kg induced a reduction of 50% in parturition index and an increase of 74% in postimplantation
losses index. The in vitro test showed that uteri from rats treated with 7.5 mg/kg of the extract presented
a 50% reduction on contraction induced by arachidonic acid.
Conclusion: The exposure of aqueous extract of Morinda citrifolia in Wistar rats induced reproductive
toxicity in nonlinear dose–response.
© 2008 Elsevier Ireland Ltd. All rights reserved.

1. Introduction fruit powder and commercial Noni-derived products was investi-

Empirical use of medicine derived from plants has been widely
disseminated since ancient times to treat a wide range of diseases.
In the last decades, the interest in alternative therapies has raised
markedly in a worldwide shape. The occurrence of side effects from
plant derived medicines, when used in an appropriate manner, are
relatively less frequent when compared to synthetic drugs. How-
ever, experimental data have shown that they are not absent of
adverse reactions even in these cases, which makes toxicological
controlled studies necessary to assess their safety (Calixto, 2000).
Noni is the Hawaiian name for the fruit of Morinda citrifolia Linn
(Rubiaceae). It is a native plant from Southeast Asia to Australia and
is cultivated in Polynesia, India, Central and northern South Amer-
ica (Chan-Blanco et al., 2006). The Polynesians have been using the
Noni plant for food and therapeutically for more than 2000 years.
It is employed nowadays in the empirical medicine to treat various
affections (Wang et al., 2002; Mc. Clatchey, 2002; Chan-Blanco et
al., 2006). Furthermore, it is largely sold as a food supplement.
Noni has recently been the object of many claims concerning
its nutraceutical properties (chemical characterization of the Noni
∗ Corresponding author.
E-mail address: pdalsenter@ufpr.br (P.R. Dalsenter).
gated by Potterat et al. (2007), and various publications have shown
that Noni can be used to relieve different diseases. Despite of this
reputation and the market around the Noni, consumption of this
fruit is currently high, not only in the producing countries, but also
in the United States, Japan and Europe (Chan-Blanco et al., 2006).
The use of products derived from plants as medicinal purposes
is common for women during gestation and lactation periods. The
great majority of the products derived from plants do not possess
pre-clinical studies of reproductive toxicity; therefore the effect of
these products on the reproductive system is unknown.
Many chemical substances can disrupt the functions of the
endocrine system of animals, including human species. Natural
products derived from plants and food supplementary compounds
are also related to an endocrine disrupting potential (Gray et al.,
2004). Since the exposition to chemical compounds that alter the
function of the endocrine system might be deleterious to preg-
nancy (Baker, 2001), studies focusing the reproductive toxicology
of chemical compounds are essential to provide reliable data about
(anti)estrogenic activities and possible toxic effects (Clode, 2006).
The increase of different forms of Morinda citrifolia uses by
various communities worldwide, and the absence of reproductive
toxicology tests about this plant, it has become increasingly impor-
tant to accomplishment of experimental protocols with objective
to investigate possible endocrine activity and toxic effect on the

0378-8741/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2008.10.019
230 J.C. Müller et al. / Journal of Ethnopharmacology 121 (2009) 229–233
reproductive system. Thus, the aim to perform the assessment of
toxicological reproductive risk of Morinda citrifolia, the aqueous
extract obtained from the fruit of Morinda citrifolia was adminis-
tered to female Wistar rats in order to assess the possible estrogenic
or antiestrogenic activity and their influence on the female repro-
ductive tract after exposure during critical periods of development.
Toxicological tests were developed following the experimental
guidelines established by the US EPA (United States Environmental
Protection Agency).
2. Materials and methods
2.1. Animals
Wistar rats were obtained from the Federal University of Parana
and maintained in controlled conditions at 22 ± 2 ◦ C and a constant
12 h light/dark cycle. Standard pellet food (Nuvital, Curitiba/PR,
Brazil) and tap water were available ad libitum. All animal studies
were carried out in accordance with the Guide for the Care and Use
of Laboratory Animals as adopted by the Department of Pharma-
cology of the Federal University of Parana (Protocol number: 156).
The experimental protocols were elaborated and developed based
on the principle of the three R’s (Refine, Reduce and Redesign), that
is, were used the lowest number of animals possible in order to
determine statistical differences; the protocols developed do not
overlap on the objective of the survey (have different investiga-
tive goals, which are complementary), and chose the development
of in vitro tests that could complement the research activities in
vivo. Moreover, the animals were handled only when necessary by
investigator trained in our laboratory, and were not exposed to any
kind of pain or stress caused by lack of food, water, variation in
temperature or presence of noise.
2.2. Morinda citrifolia extract
Morinda citrifolia fruits were harvested in southern India, in
April 2005, and the preparation of extract was in June 2005. Dried
Morinda citrifolia fruits were extracted with demineralized water
at 95–100 ◦ C for 3 h and filtered (for three consecutive times). The
three extracts obtained were mixed and then were concentrated
and dry under vacuum at 60–70 ◦ C. The dry extract was pulver-
izated, sieved, blended and packaged. The extract was standardized
in accordance with the content of polysaccharides (it must contain
at least 30% of polysaccharides).
2.3. Substances and doses
For the accomplishment of all the protocols, Morinda citrifo-
lia L. dry aqueous extracts were supplied by Gamma importation
and exportation Ltda (São Paulo/Brazil; 44.92% of polysaccha-
rides, lote: E06050117) and divided in aliquots, which were
protected from light and stored at 4 ± 3 ◦ C. The Morinda citrifolia
extract was dissolved in distilled water (vehicle) and admin-
istered by gavage in a volume of 5 mL/kg. In each study one
group served as vehicle control, and the other three groups were
treated with different doses of aqueous Morinda citrifolia extract,
based on the therapeutic doses (500 mg/kg) for human adult
patients (70 kg). The doses (mg/kg/day) managed for rats were:
7.5 (therapeutic dose), 75 (therapeutic dose × 10) and 750 (ther-
apeutic dose × 100). For the accomplishment of the uterotrophic
assay, estradiol (17-␣-ethynylestradiol, 95% pure; C20 H24 O2 ) was
obtained from Sigma–Aldrich (Steiheim, Germany) and dissolved
in canola (Brassica napus) oil (vehicle) and administered by gavage
at the dose of 0.4 mg/kg/day (Andrade et al., 2002) in a volume of
5 mL/kg, tamoxifen (tamoxifen citrate, 99.5% pure; C26 H29 NO) was
obtained from Galena Laboratory (Curitiba/Brazil) and dissolved
in distilled water (vehicle) and administered intraperitoneally at
the dose of 1 mg/kg/day in a volume of 5 mL/kg. To investigate the
Morinda citrifolia extract effect on the contractility of isolated uteri
of pregnant rats, oxytocin (ampoules, 5 UI/mL; C43 H66 N12 O12 S2 )
was purchased from União Química Farmacêutica Nacional S/A
(Pouso Alegre/Brazil) and used in the concentration of 10 mUI, and
arachidonic acid (sodium salt > 99% pure, molecular weight: 326.5;
C20 H31 O2 Na) from Sigma–Aldrich (Steiheim, Germany) and dis-
solved in absolute methyl alcohol and used in the concentration of
0.3 mM. The used concentrations of oxytocin and arachidonic acid
correspond to the concentrations next to the EC50 (effective con-
centration 50%) and they were selected from the accomplishment
of contractile-response.
2.4. Uterotrophic assay
Experimental groups of immature female rats with 21 ± 1
postnatal day were formed (8–9 animals per group) to investi-
gate a possible (anti)estrogenic activity of the Morinda citrifolia.
The immature females rats were randomly assigned to different
experimental groups and were treated daily for three consecutive
days with Morinda citrifolia extract (7.5, 75 and 750 mg/kg/day).
One group was treated with distilled water to serve as nega-
tive control, while another group received 17-␣-ethynylestradiol
and was used as a positive control for estrogenicity. The pos-
sible antiestrogenic activity was tested by treatment to other
three groups with the same doses of Morinda citrifolia extract
to female previously treated with 17-␣-ethynylestradiol. The last
group received tamoxifen after 17-␣-ethynylestradiol and served
as positive control for antiestrogenicity. Twenty-four hours after
the last treatment, the animals were weighed and killed by cer-
vical dislocation. Uteri were excised, trimmed free of fat, pierced,
and blotted to remove fluid. The body of each uterus was cut just
above its junction with the cervix and at the junction of the uter-
ine horns with the ovaries. Wet uterus weight was determined
and expressed as relative weight (wet uterus weight × 100/body
weight).
2.5. In utero and lactational assay
Pregnant rats were treated by gavage with Morinda citrifolia
extract (7.5, 75 and 750 mg/kg/day) in a volume of 5 mL/kg during
pregnancy and lactation period (from day 8 of pregnancy to day 21
of lactation).
• Mating
Female Wistar rats were mated overnight at the proportion of
three females to each male. Vaginal smears were collected daily
and examined in optics microscopy for the presence of sperm.
The day of sperm detection in vaginal smears was considered
day 0 of pregnancy. The mated females were randomly assigned
to different experimental groups and treated during pregnancy
and lactation periods.
• Maternal and reproductive outcome data
Maternal body weights were measured on 0, 5, 10, 15, and
20 pregnancy days and the dams were evaluated for gain of
corporal mass (considering that mass of day 0 of pregnancy
as 100%). At weaning the dams were killed by cervical dislo-
cation, and selected organs were removed and weighed (liver,
kidneys, adrenal glands, uterus and ovaries). Organ weights were
reported as absolute and relative and were calculated based on
the body weight, according to the formula: organ weight/body
weight × 100.
 J.C. Müller et al. / Journal of Ethnopharmacology 121 (2009) 229–233 231

The following data also were recorded: pregnancy length,

implantations number, litter size and birth weight. In addition,
parturition index [(number of females that delivered/number of
female with pregnancy evidence) × 100)], live birth index [(num-
ber of live offspring/number of offspring delivered) × 100], and
postimplantation losses ([number of implants − number of live off-
spring] × 100/number of implants) were evaluated. The females
that had not given birth until day 25 of pregnancy were sacrificed
for observation of fetuses and number of implantations.
Fig. 1. Test for antiestrogenicity (uterotrophic assay). The columns represent
mean ± S.E. of the relative uterus weight of immature females rats. Number between
2.6. Effect on the contractility of isolated pregnant rat uterus parentheses = number of animals. *p < 0.05; **p < 0.01 and ***p < 0.001 (ANOVA –
Bonferroni).
Female rats were mating as described previously and the mated
females were randomly assigned to different experimental groups.
Pregnant rats were treated daily from day 8 to 21 of pregnancy with
Morinda citrifolia extract (7.5, 75 and 750 mg/kg/day) and killed at
the 21st day of pregnancy by cervical dislocation. The uterus was
immediately removed, placed in nutritional liquid Krebs-Henseleit,
and cleaned of fat and excessive connective tissue. Fetuses were
removed from the uterus and the myometrium was transversally
sectioned in strips of approximately 5 mm of length from the cen-
tral portion of each uterine horn, and each of the two obtained
strips was submitted to different experimental conditions. Uterine
strips were placed in a 10-mL organ bath containing nutritional
liquid Krebs-Henseleit maintained at 32 ◦ C and continuously aer-
Fig. 2. Body weight gain (%) of dams exposed to Morinda citrifolia extract from day
ated with 95% O2 and 5% CO2 . Uterine strips were subjected to
8 to day 21 of pregnancy. Values represent percentage mean ± S.E.; n = number of
an optimal resting force of 1 g and a time of 60 min was reserved dams.
to equilibration period. The uterine strips were initially submit-
ted to a contraction with KCl (80 mM) to verify the viability of the
3.2. In utero and lactational exposure
tissue, and the response was considered as 100%. After 30 min,
tissues were directly stimulated with arachidonic acid (0.3 mM)
None of the doses administered influenced either the pregnancy
or oxytocin (10 mUI). In between curves, a time of 30 min was
length, number of implants, litter size, or live birth index (Table 1).
respected and the nutritional solution was renewed every 10 min.
However, the exposure to the aqueous extract of Morinda citrifolia in
Contractile isotonic responses of uterine strips were recorded using
the dose of 7.5 mg/kg induced a decrease of 50% on the parturition
a Kymograph and converted into percentage, compared with KCl
index and postimplantation losses index of 74% (Table 1). The body
response. That procedure was repeated twice to allow a medium
weight gain of dams exposed to different doses of Morinda citrifolia
value for the contraction induced by oxytocin and arachidonic
aqueous extract during pregnancy did not differ to control group
acid. The nutritional liquid Krebs-Henseleit presents the follow-
(Fig. 2). Likewise, the absolute and relative masses of the liver, kid-
ing composition (concentrations in mM): NaCl (133), KCl (5.0),
neys, adrenal glands, ovaries and uterus did not differ among the
CaCl2 (2.5), MgSO4 (1.3) KH2 PO4 (1.2), NaHCO3 (20) and Glucose
groups (Table 2).
(10).

3.3. Effect on the contractility of isolated pregnant rat uterus

2.7. Statistical analysis
The treatment of female Wistar rats from day 8 of pregnancy
Parametric data were analyzed by analyses of variance (ANOVA)
to day 21 of lactation with the aqueous extract of Morinda citrifolia
and differences between groups were assessed by the Bonferroni
did not alter the contractility of the uterine smooth muscle induced
test. Nonparametric data were analyzed by Kruskal–Wallis fol-
by oxytocin in any of the doses tested (Fig. 3). However, the dose of
lowed by Dunn’s test. The parturition index was analyzed using
7.5 mg/kg of Morinda citrifolia extract caused a significant reduction
the chi-square test. Differences were considered to be statistically
(50%) in the arachidonic acid-induced uterine contraction when
significant at a probability level of 5% (p < 0.05).
compared to the control group (Fig. 4).

3. Results

3.1. Uterotrophic assay

The relative uterine weight did not differ significantly between

the groups that received Morinda citrifolia extract doses and the
vehicle group, indicating that the aqueous extract of Morinda citri-
folia did not possess estrogenic activity in the doses tested in our
study (data not show). However, the relative uterine weight of the
animals that received 17-␣-ethynylestradiol associated with the
Fig. 3. Effect of a commercial extract of Morinda citrifolia fruit on uterine contractil-
aqueous extract Morinda citrifolia (7.5 mg/kg) was reduced in rela-
ity induced by oxytocin. The dams were exposed to Morinda citrifolia extract during
tion to the 17-␣-ethynylestradiol group, showing an antiestrogenic from day 8 to day 21 of pregnancy. The columns represent mean ± S.E. Number
effect to the extract in the dose indicated (Fig. 1). between parentheses = number of animals.
232 J.C. Müller et al. / Journal of Ethnopharmacology 121 (2009) 229–233

Table 1
Pregnancy outcome of dams treated daily with Morinda citrifolia extract from day 8 of pregnancy to day 21 of lactation.

Variable Vehicle Morinda citrifolia extract (mg/kg)

7.5 75 750

Pregnant dams/parturient 07/06 08/04 12/12 10/10

Pregnancy length (days) 22.3 ± 0.2 22.6 ± 0.3 22.7 ± 0.1 22.4 ± 0.2
Number of implants 11.3 ± 0.8 13.3 ± 1.6 9.9 ± 0.8 11.3 ± 0.7
Live birth index (%) 100.0 ± 0.0 75.0 ± 18.9 88.0 ± 7.3 88.0 ± 9.8
Parturition index (%) 85.7 ± 0.0 50.0 ± 0.0a 100.0 ± 0.0 100.0 ± 0.0
Postimplantation losses (%) 19.9 ± 13.9 74.1 ± 12.8b 32.7 ± 9.6 24.2 ± 8.6
Litter size 10.3 ± 1.2 9.2 ± 1.8 7.5 ± 1.2 10.5 ± 0.6
Birth weight (g) 6.3 ± 0.1 6.1 ± 0.1 6.2 ± 0.1 6.3 ± 0.1

Note: values represent mean ± S.E. and (%) represent percentage mean ± S.E. Data were analyzed using the dams as the statistical unit.
a
p < 0.01 (chi-square test).
b
p < 0.01 (ANOVA – Bonferroni).

The uterotrophic assay, recommended by EDSTAC (Endocrine

Fig. 4. Effect of a commercial extract of Morinda citrifolia fruit on uterine contrac-
tility induced by arachidonic acid (0.3 mM). The dams were exposed to Morinda
citrifolia extract from day 8 to day 21 of pregnancy. The columns represent per-
centage mean ± S.E. Number between parentheses = number of animals. *p < 0.05
(Kruskal–Wallis – Dunn).
4. Discussion
A remarkable amount of evidence suggests that disruption of the
female reproductive system can induce adverse effect in gestation.
Data show that approximately 50% of human conception fails to
reach delivery. Methods that detect the beginning of gestation few
days after conception have shown that 32–34% of gestations do
not reach delivery because of fetal/embryonic losses (Zinaman et
al., 1996). The reproductive system disruption can be induced by
altering the synthesis of hormones, storage, liberation, transport or
excretion, as well as acting on the interaction of the hormone to its
specific receptor, modifying the recognition of the hormone or the
cellular response after the interaction (US EPA, 1996).
Disrupters Screening and Testing Advisor Committee), is a well-
established in vivo short-term screening assay used to detecting
(anti)estrogenicity (Baker, 2001; Clode, 2006). In the present exper-
iment, the postimplantation and postnatal exposure tests were
complementaries to the in vivo uterotrophic assay for better evalu-
ation of the toxicological risk. In vitro test systems are also suitable
mainly for the detection of classic receptor-mediated effects and it
is clear that a combination of in vivo and in vitro tests are necessary
to assess the potential endocrine activities of a substance.
In the present investigation, Morinda citrifolia shows antiestro-
genic activity in the uterotrophic assay suggesting that chemicals
present in the extract of the fruit of the Noni can interact and mod-
ulate the responses of estrogenic receptors.
The exposition in utero and lactation of Morinda citrifolia extract
did not alter the pregnancy length, the number of implants, off-
spring size and live birth index. However, the postimplantation
losses index (74%) observed with the administration of Morinda
citrifolia extract (7.5 mg/kg) indicates reproductive injury induced
during pregnancy. This parameter represents increase of the resorp-
tion index, decrease of the parturition index and also stillborn. It
is known that estrogens are very important on the development of
the secondary female sexual features, as well as in the production
of an appropriate environment to the fertilization, implantation,
nutrition of the embryo and parturition (Lindzey and Korach, 1999).
Thus, the antiestrogenic activity of Morinda citrifolia observed in
the uterotrophic assay may be disturbing the embryonary and fetal
development.

Table 2
Relative and absolute organs weights from dams exposed to Morinda citrifolia extract from day 8 of pregnancy to day 21 of lactation.

Variable Vehicle Morinda citrifolia extract (mg/kg)

7.5 75 750

Parturient dams 06 04 11 09
Body weight (g) 287.30 ± 8.83 318.15 ± 8.91 305.43 ± 7.31 303.00 ± 4.47

Absolute organs weights

Liver (g) 15.42 ± 0.57 15.12 ± 1.28 14.79 ± 0.79 15.19 ± 0.51
Kidneys (g) 0.99 ± 0.03 1.09 ± 0.03 1.03 ± 0.04 1.08 ± 0.03
Adrenals (mg) 40.67 ± 2.80 42.00 ± 4.18 38.73 ± 2.17 40.56 ± 1.89
Ovaries (mg) 25.33 ± 1.86 34.25 ± 4.55 29.00 ± 2.09 28.67 ± 3.11
Uterus (mg) 176.30 ± 22.92 306.50 ± 66.44 264.80 ± 29.91 256.10 ± 37.43

Relative organs weights

Liver (%) 5.37 ± 0.06 4.77 ± 0.43 4.82 ± 0.18 5.01 ± 0.14
Kidneys (%) 0.35 ± 0.01 0.35 ± 0.01 0.34 ± 0.01 0.36 ± 0.01
Adrenals (%) 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01
Ovaries (%) 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01 0.01 ± 0.01
Uterus (%) 0.06 ± 0.01 0.09 ± 0.02 0.09 ± 0.01 0.08 ± 0.01

Note: values represent mean ± S.E; (%) = Absolute and relative organ weights were calculated based on the body weight. Data were analyzed using the dams as the statistical
unit. It is relevant to consider that one dam which received 75 mg/kg and one dam which received 750 mg/kg Morinda citrifolia aqueous extract were sacrificed for counting
number of implantations on days 23 and 25 of pregnancy, respectively. These dams not received the treatment until weaning because their pups died after birth.
 J.C. Müller et al. / Journal of Ethnopharmacology 121 (2009) 229–233
Another significant alteration observed in our study was the sig-
nificant decrease (50%) of parturition index induced by exposure of
Morinda citrifolia extract (7.5 mg/kg). Estrogens can influence the
physiology and growth of the female reproductive system and these
properties are manifested by the expression of estrogenic recep-
tors in different regions of the ovaries, uterus, cervix and vagina.
When pregnancy is reaching the end, an increase in the levels of
estrogens and a decrease of progesterone levels occur. The estro-
gens induce the increase of the myometrium sensitivity to oxytocin
by the induction of oxytocin receptors and promote an increased
synthesis of prostaglandins (Lindzey and Korach, 1999; Jain et al.,
1999).
The in vivo antiestrogenic activity detected in the uterotrophic
test might have been responsible for mechanisms that influenced
labor. The exposition at the end of pregnancy to substances that
interfere with the actions of estrogens can alter the structural fea-
tures as well as the sensitivity of the cell of the myometrium to
induce parturition (Lindzey and Korach, 1999). Thus, the antie-
strogenic activity of the extract may have inhibited the effect of
estradiol, which is to induce the expression of receptors to oxytocin
and/or to promote a synthesis increased of prostaglandins.
To elucidate the mechanism of action related with the injury
in parturition, the effect on the contractility of isolated uteri of
pregnant rats previously exposed to the Morinda citrifolia extract
was investigated. This investigation showed less uterine contrac-
tion induced by oxytocin in dams pre-treated with Morinda citrifolia
at 7.5 and 750 mg/kg doses, but this difference was not statistically
relevant. These results indicate that the injury during parturition is
not related to blockade of receptors or reduced expression of recep-
tors to oxytocin. However, since oxytocin was provided directly in
the nutrient bath, it is not possible to predict the action of the
extract upon oxytocin synthesis or liberation. In contrast, it was
possible to observe a significant inhibition of the uterine contrac-
tion induced by arachidonic acid in animals treated with 7.5 mg/kg
Morinda citrifolia extract in comparison to the control group. These
results suggest that the exposition of dams to Morinda citrifolia dur-
ing pregnancy may impair parturition due to interference in the
COX–prostaglandin pathway.
Evidences show that there is an increase in the expression
of COX-2 in the uterus near parturition, with increased uterine
contractility and cervical ripening, suggesting that this enzyme is
responsible for the synthesis of uterotonic prostaglandins in the
myometrium. Inasmuch as estrogens have been strongly implicated
on the regulation of the expression of COX-2 (Dong et al., 1998;
Gargett et al., 2002; Albrecht et al., 2003; Tamura et al., 2004;
Hervé et al., 2006), the antiestrogenic activity of the extract may
have inhibited the expression of COX-2 with consequent decrease
of uterotonic prostaglandins synthesis and impaired parturition
mechanism, or still acted as an antagonist of prostaglandins recep-
tors. In addition, clinical trials suggest that the infusion of oxytocin
is able to induce parturition only when joined by a concomitant
raise in prostaglandin levels (Slater et al., 2002). This result is in
agreement with what was observed in vivo, expressed by the dam-
age on the parturition index, as well as with the antiestrogenic
activity.
In our work, the adverse effect in the prenatal development,
damage of parturition mechanism and in vitro uterine contractil-
ity were observed with the administration of the Morinda citrifolia
extract at the low dose (7.5 mg/kg/day), but not with higher doses
(10 and 100 × 7.5 mg/kg/day). These effects have shown to be non-
linear dose-response, and studies using smaller doses yet to be
made, as well as more tests are needed to assess the potential toxic
to the female and male reproductive system.
233
In conclusion, exposition to the extract of Morinda citrifolia
affected prenatal development and labor process, and did not
induce maternal toxicity in Wistar rats. It is suggested that the
antiestrogenic activity may be related with these effects. Neverthe-
less, mainly during the first trimester of pregnancy and lactation,
the use of products derived from the fruit of Morinda citrifolia Linn
must be conducted with extreme caution or should even not be
done at all.
Acknowledgments
We are grateful to Coordenação de Aperfeiçoamento de Pessoal
de Nível Superior (CAPES) and Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico (CNPq) for financial support. We
are also grateful to Samanta Luisa de Araújo and Eduardo Manoel
Pereira for the valuable support.
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