Moderate level fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and limbic-hypothalamic-pituitary-adrenal axis regulation in monkeys

Abstract

Background: A length polymorphism in the serotonin (5-HT) transporter gene promoter region in humans and rhesus monkeys affects functional characteristics of the brain 5-HT system. Prenatal alcohol exposure (FA-exposure) can have an impact on brain and psychosocial development that could interact with genetic endowment. This study determined whether moderate FA-exposure interacts with polymorphism in the 5-HT transporter gene to increase the incidence or severity of fetal alcohol effects in rhesus monkeys.

Methods: The offspring of monkeys who did or did not consume moderate amounts of alcohol during pregnancy were assessed for temperament as neonates and adrenocorticotropic hormone (ACTH) and cortisol (CORT) in response to mother-infant separation at 6 months of age. Serotonin promoter region genotypes (homozygous s/s or heterozygous s/l versus homozygous l/l) were determined.

Results: Prenatal alcohol exposed carriers of the s allele exhibited increased neonatal irritability and increased ACTH and CORT compared with FA-exposed monkeys homozygous for the l allele and monkeys that were not FA-exposed regardless of genotype.

Conclusions: The s allele of the 5-HT transporter increases the probability of neonatal irritability and increased stress responsiveness in FA-exposed monkeys, and this gene-environment interaction may affect psychosocial development. It is probable that FA-exposure contributes to 5-HT transporter gene-environment interactions in humans.

Figure 1

Interaction between Alcohol and 5-HTTLPR genotype on Irritability. Subjects per group: N (Alcohol, Long) = 10; N (Alcohol, Short) = 9; N (NoAlcohol, Long) = 11; N (NoAlcohol, Short) = 8. Irritability was significantly increased in the Alcohol monkeys carrying the short allele (F(1,34) = 5.79; p = 0.022) by comparison to all other groups.

Figure 2

ACTH (a. Top Panel) and CORT (b. Bottom Panel) levels before and after mother-infant separation in Alcohol and NoAlcohol monkeys carrying the s allele (Short), or l/l (Long) genotype. Time Post Separation represents baseline samples (BASE), and samples collected at 2 hr and 26 hr after separation. Subjects per group: N (Alcohol, Long) = 10; N (Alcohol, Short) = 9; N (NoAlcohol, Long) = 11; N (NoAlcohol, Short) = 8. Figure 2a. ACTH levels were highest in the Alcohol, Short group 2 hr post-separation by comparison to all other groups (F(1,36) = 4.90; p = 0.03). Figure 2b. CORT was higher overall in monkeys carrying the short versus long allele at 26 hr post-separation (F(1,36) = 5.60; p = 0.02).

Figure 3

Interaction between Alcohol and 5-HTTLPR genotype on ACTHresponse (mean difference from baseline at 2 and 26hr after mother infant separation). Subjects per group: N (Alcohol, Long) = 10; N (Alcohol, Short) = 9; N (NoAlcohol, Long) = 11; N (NoAlcohol, Short) = 8. The Alcohol, Short monkeys had the largest positive ACTHresponse to separation (F(1,34) = 8.32; p = 0.007).

Figure 4

Effect of Alcohol and 5-HTTLPR genotype on CORT response (mean difference from baseline at 2 and 26hr after mother infant separation). Subjects per group: N (Alcohol, Long) = 10; N (Alcohol, Short) = 9; N (NoAlcohol, Long) = 11; N (NoAlcohol, Short) = 8. Monkeys with the short allele exhibited increased CORTresponse to separation by comparison to monkeys with the long allele (F(1,34) = 8.78; p = 0.005).

Figure 5

Correlation between Irritability and ACTHresponse to mother-infant separation in Alcohol monkeys carrying the “s” allele, or l/l (N = 19, r = 0.588, p < 0.01). The correlation between Irritability and ACTH for l/l monkeys (Long) was r = 0.080, N = 10, p = 0.83. The correlation between Irritability and ACTHresponse for monkeys carrying the s allele (Short) was r = 0.568, N = 9, p = 0.11.