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Endocrine active compounds (EACs) have been shown to influence a number of reproductive endpoints but less is known about how they might affect other hormone dependent behaviors including anxiety and aggression. Recent evidence suggests that these effects may be mediated through the beta form of the estrogen receptor (ERbeta). Using male Long Evans rats, we sought to determine how neonatal exposure to EACs affects anxiety and aggression in adulthood. Anxiety was assessed using the elevated plus maze and aggression was assessed 8 weeks later using the resident intruder test. To gain insight into which ER subtype (ERalpha vs ERbeta) might be mediating these effects we used agonists specific for ERalpha (1,3,5-tris(4-Hydroxyphenyl)-4-propyl-1H-pyrazole (PPT)) or ERbeta (Diarylpropionitrile (DPN)) as additional treatment groups. For these experiments the synthetic EAC bisphenol-A (BPA) and the phytoestrogen metabolite equol (EQ) were used. Male neonates were injected with either 0.05 ml sesame oil (control), 50 microg estradiol benzoate (EB), 1 mg/kg DPN, 1 mg/kg PPT, 50 microg/kg BPA, or 10 mg/kg EQ daily for 4 days beginning on the day of birth (PND 0). Compared to the oil treated controls, significantly fewer open arm entries were made by the males neonatally treated with DPN, EQ, or BPA. The DPN and EQ treated males were also more aggressive compared to the controls. These findings suggest that neonatal exposure to EACs with agonistic activity on ERbeta may influence affective behavior in adulthood, including anxiety and aggression.

High doses of estradiol (E(2)) can impair spatial learning in the Morris water maze, in ovariectomized mice, but the same dose has no effect on adult castrated males. Here, we test the hypothesis that this sex difference is caused by neonatal actions of E(2). In Experiment 1, C57BL/6J pups were given daily estradiol benzoate (EB) or oil injections from the day of birth until postnatal Day 3. Adults were gonadectomized and received EB (s.c.) or oil 28 h before the first day of training, and 4 h before each of four daily training sessions on the Morris water maze. Females given oil as neonates, and EB prior to training displayed the poorest performance. Females that received EB as neonates and EB prior to training were insensitive to the deleterious effects of adult EB and performed better than males given the same hormone treatments. We conducted a second experiment using aromatase enzyme knockout (ArKO) mice. Adult male and female ArKO and wild-type (WT) littermates were gonadectomized and received either injections of oil or EB prior to and during water maze training (as described above). Hormone treatment failed to affect performance, yet, female but not male ArKO mice showed impaired learning compared to WT littermates. Thus, exposure to estradiol during neonatal development can counteract the deleterious effects of EB on adult spatial learning.

One approach to study interactions between behavior and genetics is to use inbred mice with different genetic backgrounds. To examine the effect of background on a specific gene, we conducted a series of experiments with a well-characterized knockout (KO) mouse, the estrogen receptor alpha KO (ERalphaKO). The ERalphaKO mouse has so far been examined in one inbred line, C57BL/6J. Here, we examined the behavior of ERalphaKO mice within three different backgrounds mixed with C57BL/6J; DBA/2J, BALB/c, and A/J. First, we assessed masculine sexual behavior in both intact male and testosterone-treated female offspring. More ERalphaKO males in the DBA/2J (5/12) and BALB/c (5/13) backcrosses displayed intromissions and many ejaculated as compared with males in a C57BL/6J and A/J mixed background. Many fewer ERalphaKO females than males displayed masculine sexual behavior in any of the three hybrid crosses. We assessed fertility in males from the C57BL/6J by DBA/2J cross and found that one of 12 ERalphaKO males sired a litter. Several other characteristics of sexual behavior and physiology were unaffected by genetic background in ERalphaKO mice. Our data suggest that genetic background has dramatic effects on male sexual behavior and its dependence on the ERalpha gene.