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. 2020 Apr 29;9(3):173–181. doi: 10.1093/toxres/tfaa014

Neonatal exposure to chlordecone alters female social behaviors and central estrogen alpha receptor expression in socially monogamous mandarin voles

Ting Lian 1,2,#, Xudong Zhang 4,#, Xiye Wang 2, Rong Wang 5, Huan Gao 5, Fadao Tai 3, Qi Yu 1,✉
PMCID: PMC7329170  PMID: 32670549

Abstract

Chlordecone (CD) is one of the common persistent organic pollutants in nature and has a profound impact on the environment and on public health. Accumulating evidence has demonstrated that neonatal exposure of CD influences adult physiology and behavior due to its estrogenic properties. Using socially monogamous mandarin voles as an experimental animal model, the present study aimed to evaluate the impact of neonatal exposure to CD on female social behaviors and central estrogen receptor alpha (ERα) expression in adulthood. After receiving a single subcutaneous injection with sesame seed oil (female control group), 17 beta-estradiol (E2 group), or CD group on postnatal Day 1, the social behaviors of adult animals and ERα expression in specific brain regions were assessed. The data indicated that CD or E2-treated female animals displayed increased affiliative behaviors and decreased aggressive behaviors with regard to the unfamiliar females in the social interaction test. In addition, CD or E2-treated female voles exhibited significant preferences to females over males in the sexual preference test. Moreover, CD-treated female animals exhibited higher levels of ERα expression in the bed nucleus of the stria terminalis, the central amygdala, the medial amygdala and the medial preoptic area compared with those of the control voles. The results suggested that neonatal exposure to CD may masculinize female social behaviors, possibly via CD-induced changes in the ERα expression of relevant brain regions.

Keywords: chlordecone, 17β-estradiol, sexual preference, social behaviors, estrogen alpha receptor, mandarin voles

Graphical Abstract

Graphical Abstract.

Graphical Abstract

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Introduction

Chlordecone (CD) is known as Kepone, which is a persistent organochlorine pesticide that was intensively used worldwide during the 1970s and 1990s [1]. In addition, CD can be generated from another insecticide, namely mirex (one of the cost-effective pesticides used in China for termite control that has been used until 2009) [2]. Although CD has been included in the persistent organic pollutants (POPs) prohibition list, its nonbiodegradable properties and persistence in the environment for numerous decades and centuries has caused global public health concerns [3, 4]. For example, official investigation has shown that 18.5% of 3- to 5-year-old children in Guadeloupe were exposed above the ‘no effect threshold dose’ (the reference dose, RfD) of 0.5 μg/kg/day [5]. Several epidemiological studies in Guadeloupe revealed that chronic exposure to CD, mainly below the value of the RfD, was correlated with impaired neurobehavioral development in children [6, 7].

CD has been shown to induce developmental neurotoxicity due to its well-defined estrogenic properties both in vitro or in vivo [8, 9]. In humans, pre- and postnatal chronic exposure to CD affects the development of cognition and motor function during infancy [6]. In experimental studies, exposure in utero to CD significantly increased the ratio of inner to total crossings in the open field, whereas it also significantly increased lordosis and male mounting of female rats [10]. Estrogens are known to induce masculinization of the behavior system in female animals [11, 12]. Neonatal administration of estrogens may play a key role in the organization of the synaptic connections in the brain regions that are involved in sexually differentiated behaviors during adulthood [13]. Therefore, it was predicted that neonatal CD exposure might masculinize female behavior.

Estrogen exerts its biological effects on the target tissues by binding to two forms of estrogen receptors (ERs), namely estrogen receptor α (ERα) and estrogen receptor β (ERβ) [14]. ERα is primarily involved in masculinization, whereas ERβ has a major role in the defeminization of sexual behaviors [15]. Various studies have found that exposure to estrogen analogs (such as bisphenol A (BPA) or daidzein) may lead to masculinization of behavior and changes in central ERα expression of mice [16, 17]. The neonatal period is a very critical phase in which estrogen regulates the size of the brain nuclei in a sex- and region-dependent manner. The medical preoptic area (MPO), arcuate (AR) hypothalamic nucleus, medial amygdala (MeA) nucleus and ventromedial hypothalamic nucleus (VMH) contain high levels of ERα and are implicated in several social- and reproduction-related behaviors [18, 19]. Moreover, recent studies identified ERα as a coregulator essential for neuroendocrine, sexual preference and social behaviors [19–21]. Taken together, we proposed that neonatal exposure to CD might alter the levels of ERα expression in these brain regions and subsequently influence female adult behavior, such as sexual preference and social behavior.

Mandarin voles (Microtus mandarinus) are socially monogamous rodents and form enduring pair attachments [22, 23]. Using this ideal animal model, we investigated the effects of neonatal CD treatment on social interaction, sexual preference and the expression levels of ERα in specific brain regions of adult female mandarin voles. In the present study, the most potent circulating estrogen, estradiol-17 beta (E2), was applied as a reference to study the estrogenic activity of CD in vivo. E2 is important in the activation of reproductive behaviors, and affects the masculinization of the brain region in a number of mammalian species [24]. Radhika et al. [13] demonstrated that exposure of newborn female rats to E2 resulted in irreversible masculinization as well as defeminization in the brain, whereas the animals exhibited altered reproductive behavior in their adult stage of life [13]. In addition, E2 have been shown to masculinize female social behavior [16, 25]. Therefore, the effects of estrogen treatment were investigated simultaneously to elucidate whether CD exerted an estrogenic effect on social behaviors.

Materials and Methods

Animals and neonatal treatment

The mandarin voles used in the present study were F1 generation animals (30–34 g) originally captured from the Henan province in China. The animals were maintained on a 14:10 light: dark cycle at 25 ± 3°C and in the presence of 50% average relative humidity. The animals were allowed free access to food (carrots and rabbit chow) and water and kept in polycarbonate cages (44 × 22 × 16 cm) containing cotton for nesting material. All the procedures were approved by the Animal Care and Use Committee of the Shaanxi Normal University and were in accordance with the Guide for the Care and Use of Laboratory Animals of China.

Within postnatal Day 1 (PND 1), female pups received a single subcutaneous (sc) injection (0.02 mL/mouse) with sesame seed oil (female control), E2 (10 μg/kg) or CD (15 mg/kg) and male pups that were treated with sesame seed oil served as the male control group. A minimum of eight voles per group was used. CD (type: 43579) and E2 (type: E2758) were purchased from Sigma (Sigma-Aldrich China, Inc. Shanghai, China) and were initially dissolved in sesame seed oil. The selection of these doses was based on the previous study examining the estrogen-mediated effects of CD/E2 on the reproductive function of mice [16, 26, 27]. Moreover, our unpublished studies indicated no maternal or fetal toxicity in pregnant voles exposed to single doses up to 30 mg/kg CD. The subjects were weaned on their 21st day of age and housed with the same sex and the same treatment until behavioral tests were performed. The behavioral experiments were initiated in adulthood (postnatal Days 70–80). The voles from the four groups were assessed by a battery of behavioral tests as follows: social interaction and sexual preference tests. Following the behavioral test, the estrus stage of the adult female mandarin voles was identified by the vaginal smear [28]. The data were included for diestrus female subjects.

Behavioral test

Social interaction test (SIT)

The test animals were divided into four groups (female control group, CD group, E2 group and male control group) and were observed for the SIT on PND 70. The basic experimental design was identical to that noted in a previous study [28]. Each member of the pair of voles (one experimental animal, one stimulus animal) was placed in opposite corners of an open field (80 × 40 × 40 cm). The stimulus animal was an unfamiliar, sexually naïve female animal that was approximately the same age and size as the tested animal. Following a 5 min acclimatization period, the clapboard was removed and the total duration and frequency of the specific behaviors of the tested animals were recorded for 10 min. The protocol was as follows: aggression (active fighting between two voles such as wrestling, biting or scuffling), defense (staring, retreating and submission), affiliation (contacting with another individual including staying together), investigation (approaching and sniffing the stimulus) and other nonsocial behaviors (self-grooming, digging, exploring and inactivity). Precautions were taken to avoid injury and minimize the stress of the animals involved. During a pretest, the stimulus voles were selected from voles that had never caused an active attack on any other animal. The test cage was large enough so that both the tested animal and the stimulus animal could retreat easily and exclude each other. The fights that lasted >10 s were interrupted by clicking on the side of the observed cage. Once the duration of the attacking behavior lasted >20 s and the animal did not respond to the clicking, the encounter was immediately terminated and the animals were separated physically to avoid injuries. Serious injuries (e.g. bites that drew blood) were not observed during these brief social interactions. All animals were healthy and demonstrated normal locomotor activity during an observational period of 3 days following SIT.

Sexual preferences test

A modified version of the previously established partner preference task was utilized to assess preference for an estrous female or a gonadal-intact male [29, 30]. The test apparatus consisted of three polycarbonate cages (20 × 25 × 45 cm). Two of the cages (stimulus) were placed in parallel with a third cage (neutral) and attached separately to each stimulus cage by a plastic tube (15 cm in length and 7.5 cm in diameter) [31]. The two parallel chambers included a sexually naïve, estrous female and a sexually naïve, gonadal-intact male vole, respectively (mandarin voles that were similar in age, background and weight but unfamiliar to the test animal). At the beginning of the test, the test animal (~75 days old) was placed in the neutral position of the test apparatus and habituated for 10 min. Subsequently, the plastic tubes were blocked to retain the test vole in neutral cages before the female and male were loosely tethered within their separate cages. The blockages were subsequently removed and the test was recorded for 30 min. A preference score was calculated by subtracting the time spent in the stimulus male chamber from that spent in the stimulus female chamber. The frequency of aggression, defense, affiliation, mounting and investigation of the test animal to the stimulus female and the stimulus male were also scored and analyzed [23]. All of the behaviors were recorded by a digital video camera and scored later by an experimentally blind observer using Noldus Observe 5.0 (Noldus, Wageningen, the Netherlands).

Tissue collection and immunohistochemical analysis of ERα

All the experimental animals (eight animals per group) were anaesthetized with a lethal dose of pentobarbital sodium and perfused transcardially with 0.1 M phosphate buffer and 4% paraformaldehyde (pH 7.4). The brain was collected within 3 min. Following perfusion, the brain was removed and placed in 4% paraformaldehyde for 12 h followed by immersion in 30% sucrose at 4°C overnight. Coronal sections (40 μm) were cut on a cryostat and floating sections were processed using a primary antibody and the avidin–biotin complex (ABC) method. The primary antibody was a kind gift from Santa Cruz Biotechnology. The polyclonal antibody was raised in rabbit specifically directed against a peptide mapping at the carboxy-terminal end of the ERα protein (1:100, sc-542; Santa Cruze Biotechnology, CA, USA). The secondary antibody was biotinylated using goat anti-rabbit (Boster Company, Wuhan, China). 3,3′-Diaminobenzidine (DAB) was used for visualization of ERα-ir and the counting of stained nuclei was performed using an Olympus microscope (Tokyo, Japan). For each vole, the number of ERα-ir positive neurons in the nuclei was counted. Specifically the following nuclei were used for the analysis: the AR hypothalamic nucleus, the bed nucleus of the stria terminalis (BST), the central amygdala (CE), the MeA nucleus, the medial preoptic area (MPO) and the VMH. Three representative sections from anterior to posterior that were anatomically matched between subjects were selected to minimize variability. The count of the ERα-ir neurons was performed according to the method described in a previous report [32]. A total of six brain sections for each vole were counted to quantify the ERα-ir neurons. As a negative control, the primary antibody was substituted with rabbit IgG under the same concentration and conditions (AB-105-C, R&D systems, Minneapolis, MN, USA).

The number of ERα-positive neurons was quantified from images acquired under a ×10 magnification using cell counting within a 0.01 mm2 surface area. These were averaged across three nonoverlapping sections in an evenly spaced series for each vole. An observer blind to the experimental conditions performed the entire analysis. Image acquisition was performed with a Nikon (Tokyo, Japan) camera attached to an Olympus microscope.

Data analyses

Statistical analyses were conducted with SPSS 13.0 (SPSS Inc., Chicago, USA). All data were checked for normality. The data from the SIT, preference score and immunohistochemical analysis were normally distributed and tested using the one-way analysis of variance (ANOVA) test. The behavioral responses of the female and the male animals in the sexual preferences test were further analyzed using the paired sample t test. All data were presented as mean ± SE and the significance was established at P < 0.05.

Results

Social interaction test

During the SIT, significant differences were noted with regard to the parameters associated with aggressive behavior (duration: F3, 28 = 20.2414, P < 0.001; frequency: F3, 28 = 10.180, P < 0.001), defense behavior (duration: F3, 28 = 4.53, P < 0.05; frequency: F3, 28 = 3.118, P < 0.05) and affiliative behavior (duration: F3, 28 = 7.22, P < 0.05; frequency: F3, 28 = 16.532, P < 0.05) among the different groups. The male control group had significant lower levels of aggression and higher affiliation to female stimulus than the female control group in response to female stimulus (all P < 0.05). The CD and E2-treated females engaged in a less aggressive behavior (CD-treated female: duration: P < 0.01; frequency: P < 0.01; E2 treated female: duration: P < 0.01; frequency: P < 0.01) and displayed higher levels of affiliative behavior (duration: P < 0.01; frequency: P < 0.01) compared with those of the control females. The post hoc analysis revealed that the aggressive (duration: P = 0.908; frequency: P = 0.429) and affiliative behavior (duration: P = 0.866; frequency: P = 0.816) of the CD and the E2 groups did not differ from each other. Furthermore, both types of behavior were not significantly different from the male control group (CD group vs. male control: P > 0.05 for all comparisons; E2 group vs. male control: P > 0.05) (Fig. 1).

Figure 1.

Figure 1

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Duration (A) and frequency (B) of behaviors during the social interaction test. The values are representative of the mean ± SEM. The groups that do not sharing the same letters are significantly different (P < 0.05).

Sexual preference test

The present study aimed to identify the role of CD or E2 in sexual preference by allowing voles to select between an estrous female and a gonadal-intact male partner. As shown in Fig. 2, the one-way ANOVA test revealed that the preference scores were significantly different among the groups (F3, 28 = 3.480, P < 0.01). Post hoc analysis revealed that the CD, E2 and male control groups did not exhibit significant differences (CD group vs. E2 group: P = 0.750; CD group vs. male control: P = 0.174; E2 group vs. male control: P = 0.269) with regard to the preference scores, and furthermore, that all were significantly different from the female control voles (P < 0.05 for all comparisons). The negative preference score for the female control group indicated that additional time was spent in the chamber containing the gonadal-intact male animals than in the chamber containing the estrous female animal. In contrast to these observations, the positive preference scores for the CD, E2 and male control groups indicated that the time spent in the chamber containing the estrous female animal was higher compared with that spent in the chamber containing the gonadal-intact male animal.

Figure 2.

Figure 2

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Preference scores of different groups, following the selection between a gonadal-intact male and an estrous female vole. A positive score indicates a preference for the estrous female vole, whereas a negative score indicates a preference for the sexually active male vole. The groups that do not share the same letter in each cluster were significantly different (P < 0.05).

The frequencies of aggression, defense, affiliation, mount and investigation behaviors of the test animal to the stimulus female and the stimulus male animals were analyzed. Using one-way ANOVA analysis we demonstrated significant differences between groups in the affiliation (F3, 28 = 20.147; P < 0.001) and investigation behaviors (F3, 28 = 3.073; P < 0.05). When encountering the stimulus female animal, CD-treated and E2-treated females exhibited significantly higher frequency of affiliative and investigative behaviors than the control females (all P < 0.05). When confronted by the stimulus male animal, the CD and the E2 groups indicated significantly lower levels of affiliative and investigative behaviors compared with those of the female control group (all P < 0.05). The CD/E2-treated females showed a higher frequency of affiliative and investigative behaviors in the chamber containing the female vole than that noted in the chamber containing the male vole. Furthermore, the frequencies of affiliation and investigation in the sexual preference test between the CD and the male control groups indicated no significant differences (all P > 0.05) (Fig. 3).

Figure 3.

Figure 3

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Frequency of affiliation (A) and investigation (B) in the sexual preference test. The values were the mean ± SEM (n = 8 animals per group). *P < 0.05, **P < 0.01 Significant differences of affiliation or investigation frequency were noted, during the estrous female encounter compared with those of the female control vole. #P < 0.05,##P < 0.01 significant differences of affiliation or investigation, following encounter of the male compared with those noted following encounter with the female control animals.

Measurement of ERα-ir neurons in the brain tissues

Significant differences were found in the number of ERα-ir neurons in the tissues derived from AR (F3, 28 = 6.398, P = 0.001), BST (F3, 28 = 26.367, P < 0.001), CE (F3, 28 = 66.321, P < 0.001), MeA (F3, 28 = 117.826, P < 0.001), MPO (F3, 28 = 47.456, P < 0.001) and VMH (F3, 28 = 15.826, P < 0.001) among the different groups. The expression of ERα was sexually dimorphic in the mandarin vole, with female controls expressing significantly higher levels of ERα-ir in BST, CE, MeA and MPO than male controls (all P < 0.05). Female voles neonatally exposed to CD displayed fewer ERα-ir neurons in BST (mean diff. = 18.3205, P < 0.001), CE (mean diff. = 22.3526, P < 0.001), MeA (mean diff. = 41.25, P < 0.001) and MPO (mean diff. = 13.4038, P < 0.05) than control females. There was no difference in the expression levels of ERα in these specific brain regions (BST, CE, MeA and MPO) between the CD and the E2 groups (all P > 0.05). The change trend of ERα expression in BST, CE, MeA and MPO of CD-treated females was consistent with that of the control males compared with the control female animals. (Figs 4 and 5).

Figure 4.

Figure 4

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The number of ERα-immunoreactive neurons in six brain regions from different experimental groups. The values are representative of the mean ± SEM (n = 8 animals/group). The groups not sharing the same letter were significantly different (P < 0.05).

Figure 5.

Figure 5

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Representative microphotographs of ERα-immunoreactive neurons in the AR, BST, CE, MeA, VMH and MPO tissues of mandarin voles of the four experimental groups. (1, 5, 9, 13 and 17) female control; (2, 6, 10, 14 and 18) CD-treated; (3, 7, 11, 15 and 19) E2-treated; (4, 8, 12, 16 and 10) male control. Scale bar 100 μm.

Discussion

In the present study, we demonstrated that exposure to CD and E2 during neonatal life could affect female social behaviors in adults, such as social interaction and sexual preference. CD and E2-treated females displayed significantly lower levels of aggression and higher affiliation to female stimulus, whereas they preferred to spend more time with an estrous female than with a male. The number of ERα-ir neurons in the BST, CE, MeA and MPO were altered following neonatal CD exposure and E2 exposure in a site-specific way in females. Therefore, it is inferred that neonatal CD exposure may exert estrogen-like effects on female social behaviors in female mandarin voles, possibly via CD-induced changes in the expression of ERα in the relevant brain regions.

In the social interaction test, neonatal female pups treated with CD were engaged in higher frequency of affiliation, although a lower incidence of aggressive behavior was observed following encounter with the female stimulus animal at adulthood. The effect was also similar to that induced by neonatal estrogen treatment. Furthermore, both effects were not significantly different from those noted in the male control animals. Therefore, neonatal CD treatment induced a male pattern of social behaviors in the female animals while retaining the same-sex masculinization effects. This result was consistent with previous reports indicating that female rodents exposed to other estrogenic EDCs exhibited masculinizing effects on social behaviors during social interaction tests. For example, BPA and E2-treated female mice displayed increased levels of affiliation to female stimulus mice and decreased levels of affiliation to male stimulus mice, respectively [16]. Similarly, female juvenile Sprague–Dawley rats exposed to BPA from conception to weaning indicated masculinization in two behavioral categories (play with females and sociosexual exploration) [11]. In addition, the current results were supported by certain studies in other species demonstrating that long-term exposure to the estrogenic drug 17α-acetylene estrogen reduced aggressive attacking behavior on the same-sex interaction and altered courtship behavior in the female fish [33].

We further studied the effects of CD on social behaviors by testing sexual orientation and sexual activity. When presented with a choice between proximity to an estrous female or to a gonadal-intact male in the sexual preference test, CD-treated and E2-treated females demonstrated similar preferences for the estrous female vole. Control females, conversely, preferred to spend time with the male voles. The CD group did not exhibit significant differences with regard to the preference score (an indirect index of sexual motivation) compared with those of the male control animals, suggesting that CD-treated female animals were masculinized. In addition, neonatal CD treatment significantly increased affiliation and reduced aggressive behavior of the female animals, following encounter with the female stimulus animal. This result is consistent with the study by Henley and his colleagues [25] demonstrating that neonatal female rats treated with high concentrations of estrogen spent more time in side-by-side contact with female than male animals as determined by the adult mate choice test. Moreover, previous studies have reported that prenatal/neonatal exposure of female rats to CD exhibited high levels of mounting behavior compared to female control rats [10, 34], which demonstrated the masculinizing effects of CD and was consistent with the results of the present study.

Neonatal exposure to CD caused a significant change in the neurophysiological responses of the female voles. In the current study, the expression of ERα was sexually dimorphic in BST, CE, MeA and MPO tissues compared with female animals exhibiting higher expression levels of this protein. The data were in agreement with previous reports suggesting that highly social males exhibited significantly lower levels of ERα-ir in specific brain regions compared with those of female animals [35, 36]. It is well established that estrogen produces the effect of masculinization to the brain and affects behavior during early development [13, 36]. Several effects caused by perinatal estradiol on sexual differentiation of the brain were mediated via the ERα [19, 36]. Moreover, ERα plays a major role in masculinization by regulating the estrogen signaling in the rat brain [36, 37]. Neonatal CD or E2 exposure decreased the levels of ERα in female animals in the BST, CE, MeA and MPO tissues, while a similar pattern of changes was noted with regard to the ERα levels of male control animals. No significant differences were noted between the CD and E2 groups. The presence of higher expression levels of ERα in the brain of female animals suggested that the male voles may be less sensitive to estrogens during the neonatal period. These results were consistent with previous reports demonstrating that estrogens could lead to ERα mRNA downregulation in the brain tissues of fetal animals [38]. In dwarf hamsters, low levels of ERα in the BST, CE and MeA tissues played a critical role in the expression of social monogamy, which was characterized by high levels of affiliation and low levels of aggression [39]. The present study further supported the finding that CD-treated and E2-treated female mandarin voles exhibited lower ERα expression in the BST, MeA and CE tissues and were engaged in aggressive and highly affiliative behavior in the social interaction test. The MPO is critical for the production of male-typical sexual behaviors. In addition, it has been shown that exposure of newborn female rats to E2 masculinizes MPO and affects sexual behavior [40]. Moreover, it has been reported that E2 acts in the brain by increasing the expression levels of ERα in the MPO tissues and consequently affecting male rat sexual behavior [41]. In the present study, the differences in the expression pattern of ERα-ir among the four experimental groups were associated, since the time spent with the estrous female in the partner preference test was proportional to the decrease in the expression levels of ERα. This indicated that CD/E2 induced important irreversible changes in female voles with regard to the masculinizing behavior and could further establish masculinization during the adult stage. Therefore, the effects of neonatal CD or E2 on social behaviors and sexual preference were closely associated with the alteration in the expression levels of ERα.

Conclusion

Taken collectively, the data suggested that neonatal exposure to CD and E2 resulted in masculinization of female voles, possibly by downregulating the expression of ERα in specific key brain regions. The understanding of the mechanism by which EDCs influence social behaviors and physiology is critical for the development of accurate and predictive risk assessment models for vulnerable human and wildlife populations.

Acknowledgements

We would like to thank Weige Feng and RuiJia (Shaanxi Normal University) for their untiring efforts for the preparation of this manuscript. We also thank JunxiGuo (Xi’an Gaoxin No.1 High School) for his assistance in the experimental conduct. In addition, we are grateful to Prof. Tai F.D. for his constructive comments.

Funding

The present study was supported by the grant from the Scientific Research Program Funded by the Shaanxi Provincial Education Department (No.18JK0671), Key Science and Development Program of Shaanxi province (No. 2017SF-270), the Project of Xi’an Medical University (No. 2020ZX02), Shaanxi Key Laboratory of Ischemic Cardiovascular Disease (No. 2017ZDKF11) and National Natural Science Foundation of China (No. 81903288).

Conflict of interest statement

None declared.

References

  • 1. Chaussonnerie S, Saaidi PL, Ugarte E et al. Microbial degradation of a recalcitrant pesticide: chlordecone. Front Microbiol 2016;7:2025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Wang B, Iino F, Yu G et al. HRGC/HRMS analysis of mirex in soil of Liyang and preliminary assessment of mirex pollution in China. Chemosphere 2010;79:299–304. [DOI] [PubMed] [Google Scholar]
  • 3. Legoff L, Dali O, D'Cruz SC et al. Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features. Epigenetics Chromatin 2019;12:29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Cabidoche YM, Lesueurjannoyer M. Contamination of harvested organs in root crops grown on chlordecone-polluted soils. Pedosphere 2012;22:562–71. [Google Scholar]
  • 5. Nedellec V, Rabl A, Dab W. Public health and chronic low chlordecone exposures in Guadeloupe; part 2: Health impacts, and benefits of prevention. Environ Health 2016;15:78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Dallaire R, Muckle G, Rouget F et al. Cognitive, visual, and motor development of 7-month-old Guadeloupean infants exposed to chlordecone. Environ Res 2012;118:79–85. [DOI] [PubMed] [Google Scholar]
  • 7. Boucher O, Simard MN, Muckle G et al. Exposure to an organochlorine pesticide (chlordecone) and development of 18-month-old infants. Neurotoxicology 2013;35:162–8. [DOI] [PubMed] [Google Scholar]
  • 8. Lemaire G, Mnif W, Mauvais P et al. Activation of alpha- and beta-estrogen receptors by persistent pesticides in reporter cell lines. Life Sci 2006;79:1160–9. [DOI] [PubMed] [Google Scholar]
  • 9. Multigner L, Kadhel P, Rouget F et al. Chlordecone exposure and adverse effects in French West Indies populations. Environ Sci Pollut Res Int 2016;23:3–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Laessig SA, Auger AP, Carthy MM et al. Effects of prenatal chlordecone on sexually differentiated behavior in adult rats. Neurotoxicol Teratol 2007;29:255–63. [DOI] [PubMed] [Google Scholar]
  • 11. Dessi-Fulgheri F, Porrini S, Farabollini F. Effects of perinatal exposure to bisphenol a on play behavior of female and male juvenile rats. Environ Health Perspect 2002;110:403–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Marie Y. Pollution Persistante des Sols aux Antilles par des Insecticides Organochlorés : HCH et Chlordécone Encore Pour des siEcles?, Rencontres « Sites et Sols Pollués ». Paris: ADEME (Résumé étendu), 20–21 October2009. Présentation Orale, CDROM. [Google Scholar]
  • 13. Radhika NS, Govindaraj V, Sarangi SK et al. Neonatal exposure to 17beta-estradiol down-regulates the expression of synaptogenesis related genes in selected brain regions of adult female rats. Life Sci 2015;141:1–7. [DOI] [PubMed] [Google Scholar]
  • 14. Srinivasan S and Nawaz Z.. 35 - Molecular Biology of Estrogen Receptor Action, Hormones, Brain and Behavior (Second Edition),Part III San Diego: Academic Press, 2009, 1187–1220. [Google Scholar]
  • 15. Kudwa AE, Michopoulos V, Gatewood JD et al. Roles of estrogen receptors alpha and beta in differentiation of mouse sexual behavior. Neuroscience 2006;138:921–8. [DOI] [PubMed] [Google Scholar]
  • 16. Yu CJ, Tai FD, Song ZZ et al. Pubertal exposure to bisphenol a disrupts behavior in adult C57BL/6J mice. Environ Toxicol Pharmacol 2011;31:88–99. [DOI] [PubMed] [Google Scholar]
  • 17. Yu CJ, Tai FD, Zeng S et al. Effects of perinatal daidzein exposure on subsequent behavior and central estrogen receptor α expression in the adult male mouse. Prog Neuro-Psychoph 2013;43:157–67. [DOI] [PubMed] [Google Scholar]
  • 18. Mitra SW, Hoskin E, Yudkovitz J et al. Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha. Endocrinology 2003;144:2055–67. [DOI] [PubMed] [Google Scholar]
  • 19. Yu CJ, Fang QQ, Tai FD. Pubertal BPA exposure changes central ERalpha levels in female mice. Environ Toxicol Pharmacol 2015;40:606–14. [DOI] [PubMed] [Google Scholar]
  • 20. Musatov S, Chen W, Pfaff DW et al. RNAi-mediated silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors. Proc Natl Acad Sci U S A 2006;103:10456–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Stetzik L, Ganshevsky D, Lende MN et al. Inhibiting ERalpha expression in the medial amygdala increases prosocial behavior in male meadow voles (Microtus pennsylvanicus). Behav Brain Res 2018;351:42–8. [DOI] [PubMed] [Google Scholar]
  • 22. Tai F, Wang TZ. Social organization of mandarin voles in burrow system. Acta Theriol Sin 2001;21:50–6. [Google Scholar]
  • 23. Wu R, Song Z, Tai F. Parent-offspring cohabitation after weaning inhibits partner preference and alters central oxytocin and dopamine systems in adult mandarin vole. Comp Physiol A -Neuroethol Sens Neural Behav Physiol 2018;204:593–604. [DOI] [PubMed] [Google Scholar]
  • 24. Beck LA, Wade J. Sexually dimorphic estrogen receptor alpha mRNA expression in the preoptic area and ventromedial hypothalamus of green anole lizards. Horm Behav 2009;55:398–403. [DOI] [PubMed] [Google Scholar]
  • 25. Henley C. L., Nunez A. A. and Clemens L. G., Estrogen treatment during development alters adult partner preference and reproductive behavior in female laboratory rats, Horm Behav, 2009, 55, 0–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Das SK, Taylor JA, Korach KS et al. Estrogenic responses in estrogen receptor-alpha deficient mice reveal a distinct estrogen signaling pathway. Proc Natl Acad Sci U S A 1997;94:12786–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Sanhita R, Xu F, Ping L et al. Increased level of cellular Bip critically determines estrogenic potency for a xenoestrogen kepone in the mouse uterus. Endocrinology 2007;148(10):4474–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Jia R, Tai F, An S et al. Neonatal manipulation of oxytocin influences the partner preference in mandarin voles (Microtus mandarinus). Neuropeptides 2008;42:525–33. [DOI] [PubMed] [Google Scholar]
  • 29. Frye CA, Paris JJ, Rhodes ME. Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3alpha,5alpha-THP formation in the midbrain ventral tegmental area. Behav Brain Res 2008;193:269–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Hamson DK, Csupity AS, Ali FM et al. Partner preference and mount latency are masculinized in androgen insensitive rats. Physiol Behav 2009;98:25–30. [DOI] [PubMed] [Google Scholar]
  • 31. Williams JR, Insel TR, Harbaugh CR et al. Oxytocin administered centrally facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster). Physiol Behav 1994;6:247–50. [DOI] [PubMed] [Google Scholar]
  • 32. He Z, Young L, Ma XM et al. Increased anxiety and decreased sociability induced by paternal deprivation involve the PVN-PrL OTergic pathway. Elife 2019;8: doi: 10.7554/eLife.44026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Bell AM. Effects of an endocrine disrupter on courtship and aggressive behaviour of male three-spined stickleback,gasterosteus aculeatus. Anim Behav 2001;62:775–80. [Google Scholar]
  • 34. Sierra V, Uphouse L. Long-term consequences of neonatal exposure to chlordecone. Neurotoxicology 1986;7:609–21. [PubMed] [Google Scholar]
  • 35. Cushing BS, Wynne-Edwards KE. Estrogen receptor-alpha distribution in male rodents is associated with social organization. J Comp Neurol 2006;494:595–605. [DOI] [PubMed] [Google Scholar]
  • 36. Wu MV, Tollkuhn J. Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior. Horm Behav 2017;95:3–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Kanaya M, Yamanouchi K. Defeminization of brain functions by a single injection of estrogen receptor alpha or beta agonist in neonatal female rats. Neuroendocrinology 2012;95:297–304. [DOI] [PubMed] [Google Scholar]
  • 38. Reddy RC, Estill CT, Meaker M et al. Sex differences in expression of oestrogen receptor alpha but not androgen receptor mRNAs in the foetal lamb brain. J Neuroendocrinol 2014;26:321–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Cushing BS. Estrogen receptor alpha distribution and expression in the social neural network of monogamous and polygynous peromyscus. PLoS One 2016;11:e0150373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Amateau SK, McCarthy MM. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci 2004;7:643–50. [DOI] [PubMed] [Google Scholar]
  • 41. Paisley JC, Huddleston GG, Carruth LL et al. Sexual responses of the male rat medial preoptic area and medial amygdala to estrogen I: site specific suppression of estrogen receptor alpha. Horm Behav 2012;62:50–7. [DOI] [PubMed] [Google Scholar]

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