Neonatal undernutrition induced by litter size expansion alters testicular parameters in adult Wistar rats.

Several models of maternal undernutrition reveal impairment of testicular development and compromise spermatogenesis in male offspring. The expansion of the litter size model, valuable for studying the impact of undernutrition on early development, has not yet been used to evaluate the consequences of early undernutrition in the adult male reproductive system. For this purpose, pups were raised in either normal litter (ten pups/dam) or large litter (LL; sixteen pups/dam). On postnatal day 90, sexual behaviour was evaluated or blood, adipose and reproductive tissues were collected for biochemical, histological and morphological analysis. Adult LL animals were lighter and thinner than controls. They showed increased food intake, but decrease of retroperitoneal white adipose tissue weight, glycaemia after oral glucose overload and plasma concentration of cholesterol. Reproductive organ weights were not altered by undernutrition, but histopathological analysis revealed an increased number of abnormal seminiferous tubules and number of immature spermatids in the tubular lumen of LL animals. These animals also showed reduction in total spermatic reserve and daily sperm production in the testes. Undernutrition decreased the number of Sertoli cells, and testosterone production was increased in the LL group. Mitochondrial activity of spermatozoa remained unchanged between experimental groups, suggesting no significant impact on the energy-related processes associated with sperm function. All animals from both experimental groups were considered sexually competent, with no significant difference in the parameters of sexual behaviour. We conclude that neonatal undernutrition induces histological and physiological testicular changes, without altering sperm quality and sexual behaviour of animals.

Sulfasalazine exposure during pregnancy and lactation: reproductive outcomes in male rat offspring.

CONTEXT: Sulfasalazine (SAS) is a drug prescribed for pregnant and breastfeeding women with chronic inflammatory bowel diseases. SAS treatment induces transitory infertility in both adult men and male rats. Although SAS crosses the placenta and passes into maternal milk, the consequences of maternal SAS exposure on the reproductive development of male offspring needs further study. AIMS: The current study evaluated whether maternal SAS exposure interferes with the reproductive development of male rat offspring in the neonatal, infant, pubertal and adulthood periods. METHODS: Pregnant Wistar rats (n =10/group) received 300mg/kg/day of SAS dissolved in carboxymethyl cellulose (CMC), by gavage, from gestational day 0 to lactation day 21, and 3mg/kg/day of folic acid during gestation. The control group received CMC. KEY RESULTS: During puberty, maternal SAS exposure increased the total length of seminiferous tubules, and round cells were observed in the lumen of caput and cauda epididymis. Moreover, SAS induced oxidative stress-related alterations in the testes of infant and adolescent rats. CONCLUSIONS: Although maternal SAS treatment caused reproductive alterations in infant and adolescent male rats, in adulthood, there were no impairments in sperm parameters that could compromise fertility. IMPLICATIONS: This study investigated the consequences of maternal exposure to SAS on the reproductive development of male rat offspring from birth to adulthood, employing a human-relevant dose. Thus, this study provides information for better understanding of SAS treatment during critical periods of development.

In utero and lactational exposure to triclocarban: Age-associated changes in reproductive parameters of male rat offspring.

Triclocarban (TCC) is an antimicrobial compound, widely used in personal care products, such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Studies show that TCC has been associated with some endocrine disruptions. In vitro, TCC demonstrated potent androgen-augmenting activity and aromatase inhibition. In this sense, exposure during critical periods of development (gestation and lactation) could lead to some adverse health outcomes in offspring. Therefore, the present study evaluated if maternal exposure to three different doses of TCC could interfere in the reproductive parameters of male offspring. Pregnant female Wistar rats were separated into four groups: vehicle Control (CTR); TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg (TCC 1.5); TCC 3.0 mg/kg (TCC 3.0). Dams were treated daily by oral gavage from gestational day 0 to lactational day 21. The males were evaluated in different timepoint: infancy (PND 21), puberty (PND 50) and adult life (PND 90-120). The histomorphometric analysis of testis and testosterone level were assessed on PND 21, 50, 120; sexual behavior and sperm parameters at adulthood. In the TCC 3.0 group, a decrease in the testis interstitial volume and an increase in testosterone levels were observed on PND 21. Moreover, there was a decrease in the diameter of the seminiferous tubules on PND 50, and a decrease in sexual competency in adulthood. These results suggest that exposure to a human relevant dose of TCC may interfere with reproduction and could have implications for human health.

In utero and lactational exposure to triclocarban: reproductive effects on female rat offspring.

Triclocarban (TCC) is an antimicrobial compound widely used in personal care products such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Recent studies have shown that TCC is associated with some endocrine disruptions. The aim of the present study was to evaluate if TCC exposure during critical periods of development (gestation and lactation) could lead to adverse effects on reproductive and behavior parameters of female offspring. Pregnant female Wistar rats were divided into four groups (n = 8-11/group): Control; TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg; TCC 3.0 mg/kg (TCC 3.0); and treated daily by oral gavage from gestational day 0 to lactational day 21. The female pups (F1 generation) were weaned on post-natal day 21 and included in the study. No litter-mates were used for the same group. There was a decrease in estradiol levels in the TCC 0.3 and TCC 3.0 groups. Moreover, there was a decrease in progesterone levels and an increase in pre-implantation loss in the TCC 3.0 group in adulthood. It is suggested, in this study, that the decrease in progesterone biosynthesis could interfere with implantation process. The exposure window to TCC is an important factor, as we found alterations only in the offspring.

Reproductive and possible hormonal effects of carbendazim.

This study aimed to better elucidate reproductive and possible hormonal effects of the fungicide carbendazim (CBZ) through a review of published toxicological studies as well as an evaluation of this fungicide in the Hershberger and uterotrophic assays, which are designed to detect in vivo effects of the sex hormones. The literature review indicates that CBZ induces reproductive and developmental toxicity through alteration of many key events which are important to spermatogenesis. The lower dose of CBZ (100mg/kg) evaluated in the Hershberger test increased prostate weight compared to control group but did not alter the weight of other testosterone-dependent tissues. In the uterotrophic assay, CBZ did not induce an estrogenic or an antiestrogenic effect. In the literature, it has been reported that CBZ may: (1) alter the levels of various hormones (testosterone, LH, FSH, GnRH); (2) negatively influence testicular steroidogenesis; (3) have androgenic effects acting directly in the androgenic receptors and/or increasing the expression of androgen receptors. Despite the contradictory results reported by the different studies that investigated a possible endocrine mode of action of CBZ, it seems that this fungicide may influence the hypothalamus-pituitary-gonad axis in addition to being a testicular toxicant.

Topiramate treatment during adolescence induces short and long-term alterations in the reproductive system of female rats.

Topiramate (TPM) is an antiepileptic drug used for treating epilepsy in children, and migraine in teenagers. In this context, preclinical studies with adult female rats observed reproductive system abnormalities following treatment with TPM. Additionally, exposure to endocrine disruptors during developmental plasticity periods, such as childhood and adolescence, may influence characteristics in the adult individual. This study evaluated whether treatment with TPM during developmental periods influences the reproductive system of female rats either immediately or in adult life. Female Wistar rats were treated with TPM (41 mg/Kg/day) by oral gavage from postnatal day (PND) 16-28, or PND 28-50, which correspond to childhood and adolescence, respectively, and euthanized either 24 h after the final administration or during adulthood. Treatment with TPM during adolescence induced short-term increase in uterus and ovary weights and reduction in endometrial stroma thickness. Adult animals treated during adolescence displayed reduced primordial ovarian follicles' numbers, and increased primary and pre-antral ovarian follicles' numbers. Treatment during childhood induced no short or long-term differences. These results indicate TPM treatment during adolescence is capable of inducing short and long-term alterations on the reproductive system of female Wistar rats.

Evaluation of escitalopram, sertraline, and methylphenidate in the immature rat uterotrophic assay.

Psychotropics are among the most prescribed medications. There are indications in the literature that fluoxetine (FLX; selective serotonin reuptake inhibitor [SSRI] antidepressant) and methylphenidate (MPH) could have a hormonal mode of action. This study was designed to evaluate the immature rat uterotrophic assay Substitute by (1) if sertraline (SER) and escitalopram (ESC) 2 other SSRI antidepressants would share the estrogenicity described for FLX and (2) MPH for estrogenicity and antiestrogenicity. The 18-day-old Wistar rats with were divided into olive oil, estradiol (0.3 mg/kg), estradiol + tamoxifen (10 mg/kg), SER (5, 15, or 45 mg/kg), ESC (2, 6, or 18 mg/kg), MPH (2.5 or 5 mg/kg), and estradiol + MPH groups. As expected, estradiol increased the weight of uterus, and this effect was counterbalanced by concomitant treatment with tamoxifen. The SER, ESC, and MPH had no effect on the uterus weight. The results suggest that ESC and SER do not share the estrogenicity described for FLX and that MPH does not disrupt estrogenic signaling.

Treatment with topiramate in rats during childhood causes testicular structural impairment at adulthood.

Topiramate (TOP) is a psychotropic drug prescribed for the treatment of epilepsy in children older than 2 years of age and for migraine prophylaxis in adolescents. There is evidence that TOP promotes negative effects on the reproductive system of male rats. This study aimed to evaluate the immediate and late treatment effects of TOP during childhood and adolescence on the male rat reproductive system. Two experimental groups received 41 mg/kg of TOP daily, by gavage, from postnatal day (PND) 16 to 28 (TOPc group) or from PND 28 to 50 (TOPa group). Control groups (CTRc group or CTRa group) received water daily. Half of the anim-als were evaluated 24 h after the end of treatment (PND 29 and PND 51, respectively) and the remainder were evaluated in adulthood (PND120). The following parameters were determined: anogenital distance, sperm evaluation, testis' histomorphometry and plasma testosterone concentration. At PND 120, the volume (CTRc:62.58 ± 2.13; TOPc: 54.54 ± 2.10*%, p = 0.018) and total length (CTRc: 25.48 ± 1.61; TOPc: 18.94 ± 2.41*, p = 0.035) of seminiferous tubules were decreased and the volume of interstitial tissue (CTRc:37.41 ± 2.13; TOPc: 45.45 ± 2.09*%, p = 0.018) and number of Leydig cells/testis (CTRc: 277.00 ± 36.70; TOPc: 400.20 ± 13.23*, p = 0.013) were increased in the TOPc group. The other parameters remained similar between the groups. Therefore, the present study contributes to our understanding that childhood treatment with TOP has an impact on the rat reproductive system in adulthood, suggesting that this period is more sensitive to TOP exposure than adolescence.

Sulfasalazine exposure during pregnancy and lactation induces alterations in reproductive behavior in adult female rat offspring.

AIMS: Sulfasalazine (SAS) is the first line drug in the treatment of chronic inflammatory bowel diseases in pregnant women. SAS and its metabolites cross the placenta and can be transferred through the milk. However, the long-term consequences to the reproductive system of offspring from dams exposed to SAS have not yet been studied. Thus, our study investigated the effects of SAS treatment during gestational and lactational periods on maternal care in F0 and reproductive outcomes in F1 females. MAIN METHODS: Wistar female rats (n = 10/group) received 300 mg/kg/day of SAS dissolved in carboxymethyl cellulose (CMC), by gavage, from gestational day 0 to lactation day 21 and 3 mg/kg/day of folic acid during gestation. The control group received CMC only. On PND 21, the female pups were selected for reproductive evaluation at different time points: infancy and adulthood. The reproductive parameters evaluated were installation of puberty (vaginal opening and first estrus), estrous cyclicity, reproductive organs weight, histological analysis of the ovary follicles and uterus, analysis of oxidative stress in ovarian tissue, reproductive behavior (sexual and maternal), and fertility. KEY FINDINGS: SAS treatment decreased the retrieving behavior in F0 females. The F1 females presented an increase in the lordosis score, frequency of lordosis of magnitude 3, and lipid peroxidation of ovarian tissues in both infancy and adult life. SIGNIFICANCE: The SAS effects observed in the current study represent a relevant concern for public health, as they demonstrated that treatment with SAS compromised the maternal motivation of dams and induced reproductive alterations in F1 females.

Developmental and Reproductive Outcomes in Male Rats Exposed to Triclosan: Two-Generation Study.

Triclosan (TCS) is a phenolic compound with broad-spectrum antimicrobial action that has been incorporated into a variety of personal care products and other industry segments such as toys, textiles, and plastics. Due to its widespread use, TCS and its derivatives have been detected in several environmental compartments, with potential bioaccumulation and persistence. Indeed, some studies have demonstrated that TCS may act as a potential endocrine disruptor for the reproductive system. In the current study, we are reporting on the results obtained for male rats after a two-generation reproduction toxicity study conducted with TCS. Female and male Wistar rats were treated daily by gavage with TCS at doses of 0.8, 2.4, and 8.0 mg/kg/day or corn oil (control group) over 10 weeks (F0) and over 14 weeks (F1) before mating and then throughout mating, until weaning F2 generations, respectively. TCS exposure decreased sperm viability and motility of F1 rats at the dose of 2.4 mg/kg. The effects of TCS on sperm quality may be related to the exposure window, which includes the programming of reproductive cells that occurs during fetal/neonatal development.

Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny.

Paracetamol (PAR) is an over-the-counter medicine used as analgesic or antipyretic by 40-50% of the pregnant women in different countries. Epidemiologic studies have been associating maternal use of PAR with neurodevelopmental disruption and special attention has been given to its potential to increase the odds for neurodevelopmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. Population-based research do not allow the establishment of causal relationships because variable control is weak. We aimed to evaluate the potential of PAR to induce developmental neurotoxicity in rats. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. General toxicity endpoints included dams' body weight and food intake as well as pups' body weight until weaning. Behavioral evaluation occurred at post-natal days 10 (nest seeking test), 27 (behavioral stereotypy), 28 (three chamber sociability test and open field) and 29 (hot plate and elevated plus-maze). Moreover, lipid hidroperoxide (LOOH), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were quantified in prefrontal cortex and hippocampus of 22-days-old rats. Gestational exposure to PAR impaired nest seeking behavior, augmented apomorphine-induced behavioral stereotypy and decreased rostral grooming in the elevated plus maze. Exposed female pups presented elevated vertical exploration in the open field test. No alterations were observed in LOOH, GSH or BDNF levels in the prefrontal cortex or hippocampus. Exposure regimen did not affect general toxicity parameters or pups' behavior in the hot plate and sociability tests. These data suggest PAR as a developmental neurotoxicant. Observed alterations may be relevant for neurodevelopmental disorders.

Can maternal exposure to paracetamol impair reproductive parameters of male rat offspring?

Paracetamol is a widely used medication during gestation and lactation periods for the treatment of pain and fever. Several studies have shown that exposure to paracetamol can increase the incidence of cryptorchidism and decrease testosterone production. Therefore, the present study aimed to evaluate if maternal treatment with paracetamol during gestation and gestation/lactation periods can alter reproductive and behavioral parameters in male offspring. Female Wistar rats were treated daily by gavage with water or paracetamol (350 mg/kg/day) during gestation (CTRG and PARG) or gestation/lactation periods (CTRGL and PARGL). There were significant differences in histomorphometry (increased volume and total length of the seminiferous tubules) and weight of testes (PARG group) and copulatory behavior and testosterone levels (PARG and PARGL groups) at PND 120. Therefore, the present study showed that maternal exposure to paracetamol has an impact on the reproductive system and sexual behavior of male adult offspring suggesting an impaired in sexual hypothalamic differentiation at the beginning of the development of the brain.

Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice.

Depressive disorders have a worldwide high prevalence. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. The aim of the present study was to evaluate the effects of developmental FLX exposure on sexual behavior, as well as on endocrine parameters, of male mice. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Male pups were tested for copulatory behavior and sexual incentive motivation. Male pups also had their anogenital distance, plasmatic testosterone concentration and testis, epididymis, seminal vesicle and pituitary wet weights assessed. Copulatory behavior, anogenital distance, plasmatic testosterone concentration and organs wet weights were not affected by FLX exposure. However, this exposure eliminated preference for a sexual incentive on the sexual incentive motivation test, which indicates reduced sexual motivation, a classic side effect of SSRIs in humans who take these antidepressants.

Evaluation of reproductive toxicity in rats treated with triclosan.

Triclosan (TCS) is an antibacterial agent used in a variety of consumer products such as: soaps, deodorant, and toothpaste, among others. Some studies have reported the (anti)androgenic effects of TCS in the male reproductive system, raising concerns about its effects on the reproductive axis. In this study, the (anti)androgenicity of TCS was evaluated in the Hershberger assay in 52-day old male Wistar rats. Additionally, the sexual behavior, sperm motility, sperm viability, and testicular histomorphometry were evaluated in a second protocol to investigate the reproductive effects of TCS in 49-day old male Wistar rats. The dosages were administered based on the acceptable daily intake for TCS, in addition to 3 and 10-fold higher doses. Our results demonstrated that TCS, in the doses administered, did not act as an endocrine disrupter (ED), with no (anti)androgenic effect in the Hershberger assay and without interfering with the parameters evaluated in the reproductive toxicity study.

Investigation of the potential effects of triclosan as an endocrine disruptor in female rats: Uterotrophic assay and two-generation study.

Triclosan (TCS) is a phenolic compound with antimicrobial action widely used in cosmetics and other personal care products and other industry segments. Its widespread use over the decades has made TCS one of the most commonly detected compounds in wastewater and effluent worldwide already being found in human urine, plasma and milk. In this study, the (anti)estrogenicity of TCS was evaluated in the uterotrophic assay in 18-day old female Wistar rats. In a second protocol, female rats were evaluated for the reproductive effects of TCS in a two-generation reproduction toxicity study. Female rats were daily treated by gavage with TCS at the doses of 0.8, 2.4 and 8.0 mg/kg/day or corn oil (control group) over 10 weeks (F0) and over 14 weeks (F1) prior to mating and then throughout mating, gestation and lactation until weaning of F1 and F2 generation respectively. TCS had no effect on the uterus weight in the uterotrophic assay. In the two-generation study, the TCS exposure compromised female sexual behavior, decreased maternal food consumption and increased pup grooming on TCS 2.4 group. The TCS chronic exposure also decreased the perimetrium thickness of F0 females from TCS 8.0 group and growing follicle number of TCS 2.4 females from F1 generation. Despite the some specific changes detected in the two-generation study, no impairment was observed in the uterotrophic assay and other important reproductive endpoints. In a weight of evidence evaluation, the results suggest that exposure to TCS at low doses did not act as an endocrine disruptor in the female rat reproductive system.

In utero and lactational exposure to metformin induces reproductive alterations in male rat offspring.

Metformin (MET) is prescribed for the treatment of type 2 diabetes mellitus and gestational diabetes. Although MET crosses the placenta, it is considered safe throughout gestation. However, it has been shown in humans that maternal exposure to MET increases sex hormone binding globulin levels in newborns, and in rats it decreases the testosterone concentration at gestational day (GD) 16.5. Therefore, the present study evaluated if maternal exposure to MET could interfere with reproductive parameters of male offspring. Wistar female rats were treated with MET 293mg/kg/day, by gavage from GD0 to GD21 (METG) or GD0 until lactational day (LD) 21 (METGL) and the control groups received water. Sexual behavior of male offspring was affected in both MET groups. However, a decrease in the sperm count was observed only in METGL group. These results suggest that MET exposure induced alterations in reproductive parameters of male offspring in adulthood depending on exposure time.

Chronic exposure to the fungicide propiconazole: Behavioral and reproductive evaluation of F1 and F2 generations of male rats.

Several studies have suggested that propiconazole (PROP) may be an endocrine disruptor; possibly altering the activity of the CYP51 enzyme, which is part of the cholesterol biosynthesis pathway required for the production of sexual steroid hormones. Another PROP effect is inhibition of the aromatase enzyme that converts androgens into estrogens, which could lead to negative effects on reproductive parameters. Therefore, the present study evaluated the reproductive and developmental toxicity of PROP by exposing two generations (F1 and F2) of male rats to this fungicide, since a previous study from our lab reported that PROP has anti-estrogenic and anti-androgenic activities (Costa et al., 2015) in the male parental (P) generation. The F1 males were exposed to PROP (4 or 20mg/kg) through germ cells (via the P generation), intra uterus, and lactation, following treatment by gavage from post-natal day (PND) 21 to 120, while the F2 generation was exposed through germ cells, intra uterus, and lactation. The parameters observed in both F1 and F2 generations were: body weight, anogenital distance (PND 0 and 21), ontogenic reflex, testosterone plasmatic levels, testis weight, and testicular histomorphology (PND 21); and in the F1 generation only: preputial separation (PND 40), sexual behavior, organ weights, testosterone and estradiol plasmatic levels (PND 120), sperm count and morphology, and testicular histomorphology at adulthood. In the F1 and F2 generations, PROP (4mg/kg) presented a decrease in testosterone levels, and in the F1 decreases in the vas deferens weight, without hormonal and functional changes of the reproductive organs, either at 4mg/kg or at 20mg/kg, in adulthood. Based on the results of this work, PROP did not alter the gonadal-endocrine parameters under these exposure conditions in rats.

Could neonatal testosterone replacement prevent alterations induced by prenatal stress in male rats?

The present study was designed to examine whether testosterone replacement is able to prevent some effects of maternal restraint stress--during the period of brain sexual differentiation--on endocrine system and sexual behavior in male rat descendants. Pregnant rats were exposed to restraint stress for 1 h/day from gestational days 18 to 22. At birth, some male pups from these stressed rats received testosterone propionate. The neonatal testosterone replacement was able to prevent the reduction in anogenital distance at 22 days of age observed in pups from stressed pregnant rats as well as prevents the decrease in testosterone levels during the adulthood of these animals. Testosterone replacement in these males also presented an improvement in sexual performance. In this way, testosterone replacement probably through increasing neonatal level of this hormone was able to prevent the later alterations caused by the prenatal stress during the period of brain sexual differentiation.

Reproductive parameters of female Wistar rats treated with methylphenidate during development.

Methylphenidate (MPH), a psychoactive agent that acts mainly by blocking the uptake of dopamine, is the main drug used to treat Attention Deficit Hyperactivity Disorder in children and adolescents. During development, important changes in brain architecture and plasticity occur, these changes, sensitive to exposure to stimulant drugs, are important in the control of GnRH secretion, influencing the release of sex hormones throughout the ovarian cycle. This study investigated the effects of repeated treatment with MPH during development on reproductive parameters of adult female rats. Wistar rats received MPH 2.5mg/kg, MPH 5.0mg/kg, or tap water (gavage) from postnatal day (PND) 21 to PND 60. From PND 75, one subgroup of females was selected for evaluation of estrous cycle, estradiol levels, weight of sexual organs, and histomorphological analysis of ovary follicles and uterus. In another subgroup, the sexual and maternal behaviors were evaluated at PND 90 and on lactational day 5, respectively. No significant alterations were observed in the MPH groups. This study demonstrated that repeated administration of MPH during the period corresponding to childhood to early adulthood does not interfere in the reproductive function of female rats in adulthood.

In utero and lactational exposure to fluoxetine delays puberty onset in female rats offspring.

Depression is one of the most prevalent disorders in the world and may occur during pregnancy and postpartum periods. Fluoxetine (FLX) has been widely prescribed for use during depression in pregnancy and lactation. This study aimed to investigate if in utero and lactational exposure to FLX could compromise reproductive parameters in female offspring. Wistar rats received, by daily gavage, FLX 5mg/kg or 0.3ml of water (control group) from the first gestational day until weaning (21 days). Assessments in the female offspring included: body weight, anogenital distance, vaginal opening, first estrus, estrous cycle, reproductive organs weight, uterine morphometric analyses, ovarian follicle and corpora lutea counting, estradiol plasmatic concentration, sexual behavior, maternal behavior and fertility test. Exposure to FLX delayed the puberty onset in female pups. The present study demonstrated that developmental exposure to FLX can deregulate the neuroendocrine hormonal control of female offspring during prepubertal and pubertal periods.