Table 2.

Examples of Developmental EDC Effects on the Neurobiology of Cognitive and Social Behaviors in Animals

Species	Sex	EDC Treatment (Route, Dosage)	Age at Treatment	Endpoints Tested	Brain Effect	Behavior Effect	Other Effects and Comments	Reference
Mouse	Male, female	Oral BPA (100 or 500 μg/kg/d	Gestational d 7 through P36	Behavior on open-field, elevated plus, Y-maze, novel object tests; receptor autoradiography for dopamine-1 and -2 receptors, dopamine transporter, and NMDA receptors in caudate-putamen, frontal cortex, and hippocampus	Dopamine-1 receptor binding was unaffected in caudate-putamen. D2 receptor binding was increased in the low-dose BPA group, and dopamine transporter binding was decreased in caudate-putamen; NMDA receptor binding was decreased in frontal cortex and in CA1, CA3, and dentate gyrus of the hippocampus	In open-field test, mice traveled more distance in the center; in elevated plus, mice had increased open arm entries (eg, decreased anxiety); on Y-maze, there was reduced alternation behavior; object recognition was impaired in the low-BPA-dosage group		(113)
Mouse	Male, female	Oral BPA (0.4 or 4 mg/kg/d) in oil	Gestational d 7–20 or P1–14	Behavior in open-field, light-dark transition, mirrored maze, elevated plus maze, forced swim; protein expression (Western blots) in hippocampus and amygdala	Western blots of GluR1 (AMPA receptor subunit) showed decreased protein in hippocampus and amygdala of BPA females and males; there was no effect on NR1 (NMDA) receptor subunit expression	Open field: gestational BPA increased grooming frequency in females; light-dark transition: in general, BPA decreased time in the light chamber in both sexes; mirrored maze: small effects in a sex-dependent manner; elevated plus: BPA decreased time spent in the open arms, and number of open arm entries; forced swim: BPA animals had increased immobile time; overall, effects of BPA were consistent with being anxiogenic	Table 1 of this paper summarizes effects of BPA on anxiety and locomotor activity in rodents; BW was affected by BPA: females given gestational BPA had lower BW, and lactational BPA males and females had higher BW	(279)
Mouse	Male, female	Dietary BPA (1.25 mg/kg chow) given to dams beginning 1 wk before mating; intake is estimated at 5 μg daily; all pups were cross-fostered to dams on a control diet	Gestation only	Juvenile social interactions with a age-, sex-, treatment-matched mouse (elevated plus maze; social preference); gene expression in whole embryo brain	Gene expression in whole embryo brains: Slc1a1 and Dnmt3a were increased in BPA compared with control females; Dnmt1 was decreased in BPA compared with control females; Oxtr was decreased in BPA compared with control males	BPA females had increased side-by-side behaviors, decreased self-grooming, more nose-nose sniffing, more following another animal, and more approaches; BPA males had more nose-nose sniffing and approaches; social preference and anxiety behaviors were unaffected	Plasma BPA was in a human-relevant dose range	(114)
Deer mouse	Male, female	Dietary BPA (50 mg/kg feed) given in chow to the mother beginning 2 wk before mating through weaning	Gestation and lactation	Sensory and motor function, olfaction, spatial learning and memory in the Barnes maze, exploratory and anxiety behavior in the elevated plus maze, mate choice (female chooses BPA- or control-exposed males), serum testosterone and corticosterone in males		Behavior in the Barnes maze was impaired in BPA males but not females; in the elevated plus maze, BPA decreased exploratory behaviors in males but not females; females showed a reduced sexual preference for males exposed to BPA	No effect on litter size or sex ratio in BPA compared with control litters; sensory systems were intact; in males, serum testosterone and corticosterone were not affected	(115)
Pine vole	Female	Oral DES (0.2 μg/kg/d) or methoxychlor (2 mg/kg/d) in corn oil, fed to the voles	Gestation and lactation	Mate preference, maternal behaviors, other social behaviors, oxytocin receptor binding	Oxytocin receptor binding was lower in the cingulate cortex of methoxychlor females; no effects were seen in the lateral septum, and DES had no effect on receptor binding	DES females were significantly more aggressive to a strange male; methoxychlor females tended to be less aggressive; time spent alone or with a conspecific male was differentially affected by the 2 treatments; no differences in time spent side by side with a male or in maternal behaviors	No effect on litter size, sex ratio, birth weights of pups; no effect anogenital distance; uterine weight was unaffected by DES but was reduced in methoxychlor females	(118)
Rat	Male, female	BPA (1 mg/L) in drinking water, beginning 1 wk before mating through weaning; animals received a soy-free or soy diet	Gestation and lactation	Gene expression in amygdala of juveniles; anxiety-like and exploratory behavior in juveniles and adults	In amygdala (P34), 48 genes were measured by quantitative PCR; gene expression was affected (mainly decreased) by BPA for Esr2, Mc4r, Mc3r, Tac2, Kiss1, Bdnf, Gal, and Gad2	In juveniles, BPA was associated with increased anxiogenic responses in the light-dark box and elevated plus maze in both sexes; some anxiogenic effects persisted into adulthood	No effect on litter size or sex ratio; some behavioral and gene expression effects of BPA were mitigated by the soy diet	(119)
Mouse	Male, female	Oral BPA (2, 20, and 200 μg/kg/d) in corn oil	Gestation	Maternal behavior of dams (dosed with BPA) to pups; gene expression in prefrontal cortex, hippocampus, hypothalamus on P28; DNA methylation of Esr1; social and anxiety behaviors	BPA had dose-, region-, and sex-specific effects on mRNAs of Esr1, Esr2, and Esrrg; BPA affected expression of Dnmt1 and Dnmt3a in hypothalamus and cortex, but little effect in hippocampus; Esr1 methylation was affected, especially in the prefrontal cortex of males and hypothalamus of females	BPA affected social behaviors in the home cage and disrupted play behaviors; it increased anxiety-like behavior in females and decrased it in males with overall diminishing sex differences; few effects on maternal behavior of the dosed dams		(120)
Rat	Male, female	BPA (0.1, 1 mg/L), resveratrol (5 mg/L) in drinking water	Gestation through weaning at P21	Sexual development, anogenital distance, open-field test, sexual behavior, estrous cycles, sperm counts, serum hormones, reproductive organ weights, SDN-POA, and locus coeruleus volume	The sex difference in the SDN-POA (male > female) was not affected by treatment; the sex differences in the locus coeruleus size and the number of cells (female > male) were reversed by both BPA doses and by resveratrol	Sex differences in the open-field test were abolished in the higher-BPA-dose group, due to males behaving more similarly to females	BPA had no effect on sexual development of males and females; resveratrol delayed day of vaginal opening	(121)
Rat	Male	PCBs 47 and 77 mixture, 12.5 or 25 mg/kg diet in food	Gestation through weaning	Social recognition in juveniles, conspecific-directed investigation in adults, size of PVN	PVN area was significantly smaller in young adult PCB males of both doses compared with control males	In the social recognition test (juveniles), the higher-dose PCB groups spent more time in the social box whereas the low-dose PCB and control males did not; in the social investigation test (adults), the high-dose PCB group differed modestly from other groups in one aspect of the test	No effect on food consumption, weight gain, or BW in dams; the 25 mg/kg diet males as adults were significantly heavier than other groups	(123)
Rat	Male, female	Reconstituted mix of PCBs 138, 153, and 180 (equimolar) plus PCB 126, 10 mg/kg/d given sc	Gestational d 15–19	Enzyme expression in the hypothalamus of offspring at gestational d 20 and P12, 21, and 60; timing of puberty; learning and memory (Morris water maze) and passive avoidance	Aromatase mRNA in hypothalamus was increased in PCB-treated rats only at P21 in males; mRNA of 5α-reductase-1 was lower in PCB females at P21 and in PCB males and females at P60; 5α-reducatase-2 mRNA was elevated in PCB females at P60	Spatial memory (Morris water maze) was unaffected by treatment; passive avoidance was impaired only in PCB males	BW at puberty was lower in PCB-exposed males and females; age at vaginal opening was 1 d earlier; age at testicular descent was 1 d later	(117)
Rat	Male, female	Phthalates (DEHP), 30 mg/kg BW/d in drinking water	P1 to weaning	Behavior in elevated plus maze at P30, P45, and P60	DEHP males were affected at P45 and P60 with decreased frequencies of entries into the open arm and time spent in open arm and increased time spent in the closed arm; no effect in females			(122)

Abbreviations: BW, body weight; DEHP, di-2-ethylhexyl phthalate; NMDA, N-methyl-d-aspartate; P36, postnatal day 36; PVN, paraventricular nucleus.