amitraz

Short communication

Assessment of reproductive and fertility effects of amitrazpesticide in male mice

Rawdah K. Al-Thani a,*, Aisha S. Al-Thani a, Ahmed Elbetieha b,1,Homa Darmani b

a Department of Biological Science, University of Qatar, P.O. Box 2713, Doha, Qatarb Department of Applied Biology, Faculty of Science, Jordan University of Science and Technology, Irbid, Jordan

Received 1 July 2002; received in revised form 30 October 2002; accepted 4 November 2002

Abstract

Forty adult male Swiss mice were exposed to tap water containing 0, 40, 80, or 160 ppm amitraz for 12 weeks. Based

on fluid consumption the mice received an average of 0, 5.429/0.47, 10.569/0.97, and 20.399/2.17 mg/kg/day amitraz,

respectively. The average body weights gains and fluid consumption were significantly decreased in males exposed to

amitraz pesticide. Fertility was significantly reduced in male mice ingesting 10.569/0.97 or 20.399/2.17 mg/kg/day

amitraz in that the number of females impregnated by them was significantly reduced. The number of viable fetuses was

significantly reduced in females mated with males that ingested 10.569/0.97 or 20.399/2.17 mg/kg/day amitraz. A

significant increase in the total number of resorptions and the number of females with resorptions was observed in

females impregnated with the exposed males. Absolute testis weight was significantly decreased at 10.569/0.97 mg/kg

concentration. The weight of the epididymis was decreased in test males ingested 20.399/2.17 mg/kg amitraz. The

seminal vesicles weights were significantly increased in male mice ingested 10.569/0.97 or 20.399/2.17 mg/kg/day

amitraz. Similarly, the preputial gland weights were increased in males that ingested 5.429/0.47 or 10.569/0.97 mg/kg

and decreased in males ingested 20.399/2.17 mg/kg amitraz. Testicular sperm counts and daily sperm production were

significantly decreased in males that ingested 10.569/0.97 or 20.399/2.17 mg/kg/day amitraz. Epididymal sperm counts

were significantly decreased in exposed male’s at 10.569/0.97 or 20.399/2.17 mg/kg amitraz. These results strongly

suggest that exposure to amitraz pesticide have an adverse effect on the fertility and reproductive system of male mice.

# 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Amitraz; Fertility; Male mice

1. Introduction

Amitraz is a trade name of triazapentadiene

compound (N ,N ?-[(methylimino) dimethylidy-

ne]di-2,4-xylidine), a member of the formamidine

class chemical family (The Agrochemicals Hand-

book, 1994). It is an insecticide and acaricide used

* Corresponding author. Tel.: �/974-485-2709; fax: �/974-

4800-786.

E-mail address: [email protected] (R.K. Al-

Thani).1 Present address: Department of Biological Science,

University of Qatar, P.O. Box 2713, Doha, Qatar (Sabbatical

Leave).

Toxicology Letters 138 (2003) 253�/260

www.elsevier.com/locate/toxlet

0378-4274/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.

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to control red spider mites, leaf miners, scaleinsects and aphids. On cotton it is used to control

bollworms, white fly and leaf worms. On animals

it is used to control ticks, mites, lice and other

animal pests (Thomson, 1993; Budavari, 1989).

The US Environmental Protection Agency classi-

fies amitraz as class III-slightly toxic (U.S. EPA,

1987). The oral LD50 for mice is greater than 1600

mg/kg. Long term feeding studies show thatamitraz is not carcinogenic in rats. However, it

can cause tumors in female mice (Hayes and Laws,

1991). At high doses, amitraz can reduce the

function of the hypothalamus (U.S. EPA, 1987).

Animal studies have shown that amitraz may have

serious effects on fertility and reproduction. Fe-

male mice treated orally for 5 days with 50 mg/kg/

day of amitraz and then mated showed a slightincrease in loss of fetuses and a decrease in the

number of living offspring (Hayes and Laws,

1991). In another study female mice who received

400 mg/kg/day of amitraz in their diet for up to 30

weeks, showed a significant increase in the time

they were sexually receptive (Hayes and Laws,

1991). Following acute exposure in female rats,

both amitraz and chlordimeform (CDF), anotherformamidine, have been found to block the

luteinizing hormone (LH) surge and thus delay

or block ovulation (Goldman et al., 1991; Cooper

et al., 1999), most likely as a consequence of their

activity as a-noradrenergic antagonists. Further-

more, in the male mice CDF was observed to

decrease circulating LH and testosterone concen-

trations and to dramatically suppress the release invitro of gonadotropin releasing hormone from

hypothalamic tissue (Goldman et al., 1990). How-

ever the effects of acute dosing didn’t persist, and

serum hormonal levels in the male returned to

normal within 4 days. In addition yohimbine, an a2-adrenergic antagonist, has been found to attenu-

ate the delayed lethality induced by amitraz

(Moser and Macphail, 1985). Furthermore, fema-le’s rabbit that received 25 mg/kg/day of amitraz

from days 6�/18 of pregnancy had fewer and

smaller litters (Meister, 1994).

Amitraz has been shown to be teratogenic in

laboratory animals. In one study, rats treated with

12 mg/kg/day of amitraz from days 8�/20 of

pregnancy, the offspring were heavier but had

less bone development than the offspring ofuntreated rats (Hayes and Laws, 1991). However,

an EPA study indicates that the highest dose at

which amitraz has no observable effect on test rats

offspring (teratogenic NOEL) is 12 mg/kg/day.

Recently, the teratogenic effect of amitraz has

been demonstrated in the developing frog Xenopus

laevis , embryos (Osano et al., 2002).

Amitraz is broken down rapidly in soil contain-ing oxygen. The half-life in soil is less than 1 day.

Degradation occurs more rapidly in acidic soils

than in alkaline or neutral soils (Kidd and James,

1991).

Available data suggest that amitraz, following

absorption into the blood, is not readily absorbed

into tissues, and is mostly excreted unchanged via

the urine (Kidd and James, 1991; U.S. EPA, 1987;Hayes and Laws, 1991).

Although pesticides like amitraz may be valu-

able in agriculture, many pesticides or their break-

down products can be found in trace amounts or

higher levels in air, soil and water. Environmental

exposure to these agents may cause serious health

risks including infertility. The objective of this

study is to further evaluate the effect of amitrazpesticide on fertility of male mice.

2. Materials and methods

2.1. Animals

Forty adult male Swiss mice, at day 60 of age,weighing approximately 32 g were used in this

study. They were raised in the animal house unit in

the Faculty of Medicine at Jordan University of

Science and Technology under controlled tem-

perature of 219/1 8C in 12 h light, 12 h darkness

schedule (lights on 06.00�/18.00 h). Food (manu-

factured by the Faculty of Veterinary Medicine at

Jordan University of Science and Technology,Irbid, Jordan, according to standard recipes) and

water were offered ad libitum.

2.2. Administration of amitraz pesticide

Amitraz pesticide in the form of emulsifiable

concentrates (200 g/l) was purchased from the

R.K. Al-Thani et al. / Toxicology Letters 138 (2003) 253�/260254

Veterinary and Agricultural Products Co. Ltd(VAPCO), (Amman, Jordan) and was diluted

with tap water on daily bases to the appropriate

concentrations of 40 ppm (1/40 of the LD50), 80

ppm (1/20 of the LD50) and 160 ppm (1/10 of the

LD50). Male mice were randomly assigned into

groups of 10 animals each and allowed ad libitum

access to tap water containing amitraz. Control

male mice were given tap water only. Based onfluid consumption the mice exposed to 0, 40, 80,

and 160 ppm amitraz received an average dose of

0, 5.429/0.47, 10.569/0.97, and 20.399/2.17 mg/kg/

day amitraz, respectively. Mice oral LD50 for

amitraz is around 1600 mg/kg (Meister, 1994).

2.3. Fertility test

Animals were observed daily from the first day

of exposure to amitraz for clinical signs of toxicity.

Their water consumption was measured every day

and the body weights every week. Fertility was

estimated in adult male mice exposed to 0, 40, 80

and 160 ppm amitraz for 12 weeks. After 12 weeks

of amitraz ingestion, dosing was discontinued and

each treated male was placed in an individual cagewith two virgin untreated females of the same

strain. They were left together for 10 days during

which two estrus cycles should have elapsed

(Rugh, 1968). Adult male mice ingested amitraz

as well as the control males, were then removed

and sacrificed for further evaluations. Ten days

later, the mated females were killed by cervical

dislocation under light ether anesthesia and thefollowing measurements were recorded: number of

pregnant females, number of implantation sites,

number of viable fetuses, number of resorptions,

and number of females with resorptions. It is

noteworthy to point out that 3 animals out of 10

and 1 out of 10 were died during the third week of

exposure to 160 and 80 ppm amitraz, respectively,

most likely due to amitraz toxicity. Other sign ofamitraz toxicity observed in this study was an

increase in aggressive behavior, as evidenced by

fighting and resultant cutaneous lesions, among

males treated at 160 ppm. Food consumption did

not differ significantly between the control and

treated groups (data are not shown).

Procedures employed in the use and sacrifice ofmice were in accordance to the NIH Guide for the

Care and Use of Laboratory Animals.

2.4. Evaluation of reproductive organs weights

Amitraz exposed and control males were sacri-

ficed after 12 weeks of amitraz ingestion and the

10 days period of mating. The following organs

were excised and weighed: paired testes, seminal

vesicles (stripped of seminal fluid), epididymis and

preputial glands.

2.5. Testicular and epididymal sperm counts

The excised left testis and epididymis were

weighed. Testis from each mouse was placed in

10 ml of normal saline (0.9% sodium chloride) and

refrigerated for later homogenization for sperma-tid count. Epididymis was placed in 10 ml of

normal saline (0.9% sodium chloride) and refri-

gerated for later homogenization for epididymal

sperm count.

Sperm count was performed according to the

method of Amman and Lambiase (1969). Briefly,

the excised left testis or epididymis from each

mouse was sectioned by a disposable blade in 4 mlof normal saline in a conical glass petri dish, and

then minced using a manual glass homogenizer.

The homogenate was mixed using a vortex mixer

and the number of sperm measured using a

hemocytometer. Epididymal sperm counts were

expressed as number of sperms per mg of epidi-

dymis. Testicular spermatid counts were expressed

as the number of spermatids per mg of testis. Theestimate of daily sperm production (DSP) per

testis per day was calculated based on a factor of

4.84 as described by Vom Saal et al. (1998).

2.6. Statistical analysis

Data are expressed as mean9/S.D. Differences

between control and test groups were analyzed

using either Student’s t-test or Fisher’s exact test.

A P -value less than 0.05 was considered signifi-

cant.

R.K. Al-Thani et al. / Toxicology Letters 138 (2003) 253�/260 255

3. Results

3.1. Effect of amitraz on body weight gain and fluid

consumption

Table 1 presents the effects on body weight and

fluid consumption of male mice exposed to 0, 40,

80, and 160 ppm amitraz. Body weight gain was

reduced in males that ingested an average of10.569/0.97 (P B/0.05) or 20.399/2.17 mg/kg

(P B/0.001) amitraz. Fluid consumption decreased

in males that ingested 5.429/0.47 (P B/0.001) and

10.569/0.97 (P B/0.0001) or 20.399/2.17 mg/kg

amitraz.

3.2. Effect of amitraz on fertility

The results presented in Table 2 demonstrate the

adverse effect of amitraz on male mice fertility.

The number of pregnancies in females mated with

the test males was reduced in males that ingested

10.569/0.97 (P B/0.01) or 20.399/2.17 mg/kg ami-

traz. There were no significant differences in the

number of implantations in females impregnated

with either control or test male mice. However, thenumber of viable fetuses was reduced in females

mated with males that ingested 10.569/0.97 (P B/

0.05) or 20.399/2.17 mg/kg (P B/0.005) amitraz.

Likewise, the total number of resorptions per

group increased in females exposed to all three

concentrations of amitraz (P B/0.005). The num-

ber of females with resorptions increased when

mated with males that ingested 5.429/0.47 or20.399/2.17 mg/kg amitraz (P B/0.01).

3.3. Effects of amitraz on weights of reproductive

organs

The data presented in Table 3 show the effect of

exposure to amitraz on weights of some male

reproductive organs. Absolute testis weight was

decreased in males that ingested 10.569/0.97 mg/

kg amitraz (P B/0.01). Epididymal weights were

decreased in males that ingested 20.399/2.17 mg/kg amitraz (P B/0.005). Absolute weight of semi-

nal vesicles was increased in males that ingested

10.569/0.97 (P B/0.005) or 20.399/2.17 mg/kg

(P B/0.05) amitraz. The relative weights of seminal

vesicles were also increased in males that ingested

10.569/0.97 or 20.399/2.17 mg/kg amitraz (P B/0.

005). Absolute preputial gland weight was de-

creased in males that ingested 20.399/2.17 mg/kgamitraz (P B/0.05). However, the relative weights

of preputial glands were increased in males that

ingested 5.429/0.47 (P B/0.01) or 10.569/0.97 mg/

kg (P B/0.005) amitraz.

3.4. Effect of amitraz on testicular and epididymal

sperm counts

Table 4 presents testicular and epididymalsperm counts and DSP of male mice in the control

and the test groups. Testicular sperm counts were

decreased in males that ingested 20.399/2.17 mg/

kg (P B/0.01) amitraz. Likewise, Epididymal

sperm counts were decreased in males that ingested

any of the two higher concentrations of amitraz

(P B/0.01). The DSP was decreased in males that

ingested 10.569/0.97 (P B/0.005) or 20.399/2.17mg/kg (P B/0.0001) amitraz.

Table 1

Effect of 12 weeks ingestion of amitraz via drinking water on body weight gain and average water consumption of adult male mice

Treatment Body weight (g)a Fluid consumption (ml)a Actual dose consumption (mg/kg/d)a

Control (tap water) 35.359/2.33 5.659/0.49 �/

Amitraz (40 ppm) 33.479/2.14 4.509/0.38* 5.429/0.47

Amitraz (80 ppm) 33.269/1.46** 4.349/0.42*** 10.569/0.97

Amitraz (160 ppm) 31.969/1.70* 4.009/0.46*** 20.399/2.17

a Results are expressed as mean9/S.D.

* P B/0.001.

** P B/0.05.

*** P B/0.0001 (Student’s t -test).


4. Discussion

The present study was conducted to evaluate

any adverse effects of amitraz pesticide on fertility

and reproductive system of male mice. Amitraz

pesticide was chosen because it is widely used in

the state of Qatar as well as in many parts of the

world. The animal model used in this study was

used previously to assess the adverse effects ofpesticides on fertility and reproduction in labora-

tory animals (Costa et al., 1989).

The results presented in this study clearly

demonstrate that ingestion of amitraz for 12 weeks

caused a significant decrease in the average body

weight gain in the test males (Table 1). This

reduction in body weight gain is a clear indication

of general toxicity. This magnitude of toxicitymight have affected the animals indirectly rather

than having any specific effect on fertility. How-

ever, it has been shown that the reproductive

system of male mice was relatively resistant to

body weight decrease down to even 70% of the

body weight of control animals (Chapin et al.,

1993). Several reproductive parameters were ad-

versely affected after ingestion of amitraz by adultmale mice. The pregnancy rate was significantly

reduced in females impregnated by the test males,

which could be related to the significant reduction

in sperm count and/or to poor quality of the

semen. Furthermore, it cannot be excluded that

the pesticide could have acted directly on the testes

and influenced the androgen biosynthesis path-

way. In addition, an agent acting directly on thebrain, hypothalamus, or anterior pituitary gland

will indirectly affect the testes and possibly affect

sexual activity (Amman, 1982). There is increasing

evidence suggesting that the effects of amitraz in

mammals are mediated by its interaction with a 2-

adrenoceptors (Costa et al., 1989), and of neuro-

toxicity due to inhibition of monoamine oxidase

(Moser and Macphail, 1985). These mechanismsmight relate to inhibition of LH (Goldman et al.,

1991). Thus, if amitraz is inhibiting spermatogen-

esis, and doing so by inhibiting LH, then it would

be expected that testosterone would be lower.

However, if this is the case, it is hard to explain

the increase in the seminal vesicle weights, which is

testosterone dependent. In contrast to our results,Ta

ble

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it has been found that single or multiple doses of

CDF in the male rats had minimal effects on

gonadal function. Following two injections of

CDF (50 mg/kg), serum LH and testosterone

were significantly lower than vehicle treated con-

trols. (Goldman et al., 1990). After 4 days of

repeated CDF exposure at the same concentration.

Both hormones returned to control values (Laws

et al., 1991).

The significant increase in the number of

resorptions in females mated with test males may

be attributed to an increase in periimplantation

mortality of unhealthy fertilized ova due to

alterations in sperm quality*/a matter that needs

further investigation. The increase in the number

of resorptions in females impregnated with the test

males observed in this study is in agreement with

the results obtained by Hayes and Laws (1991).

They showed that when male mice were given 50

mg/kg/day of amitraz orally for 5 days and then

mated, the resulting embryos were significantly

less likely to grow in the mother’s uterus. In

contrast, Rehnberg and Cooper (1993) exposed

male rats to CDF for 1, 7, 14, or 21 days. At each

test interval, sexual activity was impaired (i.e.,

longer latency to first mount, first mount with

intromission, and firs ejaculation) when measured

within 1 h of treatment. However this treatment

was transient, since the CDF-treated males all

produced sperm-positive smears when housed with

a proestrous female overnight. Furthermore, the

cohabited females all became pregnant, and there

were no differences in liter size following any of

the CDF exposure periods. In addition, evaluation

of sperm number, morphology, and motility

revealed no noticeable effect of CDF on any of

Table 3

Effect of 12 weeks ingestion of amitraz via drinking water on weights of reproductive organs of adult male mice

Treatment

group

No. of

males

Absolute testes weight

(g)a (mg/10 g B.wt.)b

Epididymis

weight (mg)a

Absolute seminal vesicles

weight (g)a (mg/10 g B.wt.)b

Absolute preputial gland

weight (g)a (mg/10 g B.wt.)b

Control

(tap water)

10 0.209/0.01

(54.249/4.26)

32.319/1.66 0.139/0.02

(35.129/5.59)

0.109/0.01

(27.799/1.66)

Amitraz

(40 ppm)

10 0.199/0.01

(55.669/3.39)

31.889/1.46 0.139/0.02

(37.509/5.29)

0.119/0.01

(31.799/3.71)**

Amitraz

(80 ppm)

9 0.189/0.01**

(53.969/3.46)

31.759/1.45 0.229/0.02***

(67.609/7.50)***

0.119/0.01

(34.069/4.45)***

Amitraz

(160 ppm)

7 0.209/0.04

(61.479/9.95)

29.809/0.93*** 0.169/0.02*

(49.369/7.61)***

0.079/0.03*

(22.519/6.45)

a Results are expressed as mean9/S.D.b Relative weights.

* P B/0.05.

** P B/0.01.

Table 4

Effect of 12 weeks ingestion of amitraz via drinking water on testicular and epididymal sperm counts and DSP in adult male mice

Treatment Sperm/mg testisa (No.�/103) Sperm/mg epididymisa (No.�/103) DSPa (No.�/105)

Control (tap water) 44.929/2.70 187.949/15.25 10.319/0.62

Amitraz (40 ppm) 47.019/8.18 169.729/15.48 9.349/1.33

Amitraz (80 ppm) 41.799/4.55 146.919/21.58** 8.159/0.51***

Amitraz (160 ppm) 33.699/6.53** 143.959/15.02** 6.149/0.97****

a Results are expressed as mean9/S.D.

** P B/0.01 (Student’s t -test).

*** P B/0.005 (Student’s t -test).

**** P B/0.0001 (Student’s t -test).


these parameters. The discrepancy between our

results and their results might be due to the period

of exposure of the test males, which in our case

extended over 12 weeks. Furthermore, species

differences cannot be excluded.

The results presented in this work also show that

ingestion of amitraz pesticide by the test males

caused a significant disturbance in the weights of

the testes and other reproductive accessory glands.

The decrease in the weight of the testes and the

epididymis could be attributed to the significant

decreases in the sperm counts observed in these

organs. Such reduction in sperm counts may be

resulted from the direct effect of the pesticide on

testicular Leydig and Seroli cells causing a de-

crease in testosterone production.

The data presented in this work indicate that the

weight of the preputial gland was significantly

increased in test males ingested the pesticide at the

lower two concentrations. However, at high con-

centration the weight of these glands was signifi-

cantly decreased. It has been noted that the size

and activity of the preputial gland in rodents are

clearly influenced by a variety of steroid hormones

(Elbing, 1963). Preputial glands also produce

behavior-modulating pheromones that alter fight-

ing and other behaviors in rodents (Brain et al.,

1983). Similar studies have indicated a strong link

between male infertility and exposure to more than

50 pesticides (Cox, 1996). A significant increase in

the production of dead or abnormal sperm in mice

was reported after exposure to the pesticide

cypermethrin (Bunya and Pati, 1988) or deltame-

thrin (Bunya and Pati, 1990). Recently, we have

shown that exposure to the insecticide cyperme-

thrin, a synthetic pyrthroid, caused a significant

reduction in fertility of male Sprague�/Dawley rats

(Elbetieha et al., 2001).

Taken together, the data presented in this

work suggest that exposure to amitraz pesticide

could have adverse effects on fertility and repro-

duction in adult male mice. However, the dosage

levels of amitraz employed in this investigation are

relatively high and it is likely that human expo-

sures are very much less under normal circum-

stances.

Acknowledgements

This work was supported by the Scientific and

Applied Research Center (SARC) at the Univer-

sity of Qatar (grant No. 1/7/2001).

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