Opposing behavioural alterations in male and female transgenic TGFα mice: association with tumour susceptibility

Abstract

Summary Psychosocial factors are thought to influence risk and survival from cancer. We have previously studied specific behaviours in transgenic male CD-1 MT42 mice, which overexpress the gene encoding human transforming growth factor a (TGFa) in multiple tissues, and which Transforming growth factor a (TGFa) is a polypeptide which exhibits approximately 35% sequence homology to epidermal growth factor (EGF), and interacts with cells through the EGF receptor. Both TGFx and EGF can act as potent mitogens in a number of epithelial cell systems (Carpenter & Cohen, 1979). It has been postulated that TGFa plays an important role in neoplastic transformation, since it is highly expressed along with its receptor in many TGFa growth responsive tumour cells (Bates et al., 1988;Derynck et al., 1987;Rosenthal et al., 1986;Watanabe et al., 1987). The results of studies with transgenic CD-1 mice, in which chronic overexpression of TGFa is directed by the metallothionein (MT) promotor to multiple tissues throughout their life (Jhappan et al., 1990;Sandgren et al., 1990), have shown that male mice bearing a TGFa transgene develop a high incidence of spontaneous hepatocarcinomas at the age of 10-15 months (Jhappan et al., 1990). Other abnormalities in these animals (stomach, pancreas, etc.) have emerged as studies have proceeded.Human and animal data suggest that an ability to cope with stress influences vulnerability to develop cancer (Hilakivi-Clarke et al., 1993b;Holland, 1989;Sklar & Anisman, 1981). Perturbations in natural killer (NK) cell activity (Chuang et al., 1990;Saibara et al., 1989;Shirai et al., 1990) and steroid hormone levels (d' Arville & Johnson, 1990;Yager & Shi, 1991) may mediate the effects of psychosocial factors in cancer. We have utilised transgenic male MT42 TGFax mice in studies assessing those behaviours associated with tumourigenesis (Hilakivi-Clarke et al., 1992a). When compared with age matched non-tran sgenic control CD-1 mice, 2-3-month-old male transgenic TGFa mice spent significantly longer times immobile in Porsolt's swim test, and in aggressive behaviour (Hilakivi-Clarke et al., 1992a). The male TGFa mice also exhibited a 25% lower NK cell activity, and a 4-fold increase in the plasma levels of 17p-estradiol (E2) than the controls (Hilakivi-Clarke et al., 1992 al., 1990). This is surprising, since TGFa appears to play a significant role in mammary tumourigenesis (Bates et al., 1988;Liu et al., 1987;Sandgren et al., 1990), and female mice in other transgenic TGFa models exhibit an increased incidence of mammary tumours (Matsui et al., 1990;Sandgren et al., 1990;Stuart, 1984). The expression of TGFoa mRNA appears equally elevated in both sexes of MT42 mice (Hilakivi-Clarke et al., 1993a;Jhappan et al., 1990). To investigate behavioural changes associated with the overexpression of TGFa in the female mice, we utilised (i) Porsolt's swim test, which is thought to measure both depressive behaviour and an animal's ability to cope with stress (Garcia-Marquez & Armario, 1987;Hilakivi et al., 19...

Overexpression of transforming growth factor !a in transgenic mice alters nonreproductive, sex-related behavioral differences: Interaction with gonadal hormones.

“…Transforming growth factor a induces release of gonadotrophin-releasing hormone from the hypothalamus of female rats (Ojeda, Urbanski, Costa, Hill, & Moholt-Siebert, 1990). This may partially explain the finding that the plasma levels of E2 but not testosterone are elevated in male and female TGFa mice (Hilakivi-Clarke, Arora, et al, 1993;Hilakivi-Clarke et al, 1992). Alexi, Denton, and Hefti (1991) recently reported that TGFa stimulated dopamine uptake in rat fetal dopaminergic neurons in cell culture.…”

“…In addition, it was examined whether gonadectomy alters the expression of sex-related behavioral differences in these mice. Both male and female TGFaoverexpressing mice have been found to exhibit elevated plasma levels of 17|3-estradiol (E2; Hilakivi-Clarke, Arora, et al, 1993;Hilakivi-Clarke et al, 1992). Locomotor activity was assessed in the present study with an open-field test and aggressive behavior with the resident-intruder paradigm (Miczek, 1987).…”

“…Transgenic male CD-1 mice that overexpress human TGFα in multiple tissues exhibit elevated levels of aggressive behavior and lengthened immobility in the swim test of depressive behavior compared with equivalent nontransgenic male CD-1 mice (Hilakivi-Clarke, Arora, et al, 1992). Furthermore, transgenic TGFα CD-1 female mice appear less aggressive and spend less time immobile in the swim test than do nontransgenic CD-1 females (Hilakivi-Clarke et al, 1993). Thus, overexpression of TGFα may influence sex-related differences in behavior.…”

Comet‐FISH studies for evaluation of genetic damage of citalopram in somatic cells of the mouse

“…Like other selective serotonin reuptake inhibitors (SSRIs), transient nausea is the most frequent complaint, and decreased libido and sexual dysfunction were observed during treatment with citalopram; however, these unwanted effects can be tolerated by patients (Pollock, ; Sloot et al ., ). Although information on the carcinogenic effect of citalopram are scarce, other SSRI antidepressants in concentrations relevant to the treatment of human depression were found to promote fibrosarcomas, melanomas and mammary carcinogenesis in rodent models (Brandes et al ., ; Hilakivi‐Clarke et al ., ). Moreover, the positive association among breast cancer risk and SSRIs users has been observed in some epidemiological studies (Moorman et al ., ; Steingart et al ., ).…”

Sex differences in genetic mechanisms for mammalian brain and behavior

“…Also, the null mutants of MAO-A and NOS-1 display abnormal sexual behavior with non-estrous females. Similarly, mutants for cstrogen receptor (ER) (14,15), MAO-A, NOS-1, and transforming growth factor-a (TGF-a) (16,17) have differential effects on male and female aggression. The null mutant for NOS-1 decreases latency and increases frequency of attacks in males but not females, and that for MAO-A decrease latency to attack and increase amount of wounding in males but not females.…”