Long-term Effects Of Perinatal Exposure Research Articles

Long-Term Effects of Perinatal Exposure to a Glyphosate-Based Herbicide on Melatonin Levels and Oxidative Brain Damage in Adult Male Rats.

Concerns have been raised regarding the potential adverse health effects of the ubiquitous herbicide glyphosate. Here, we investigated long-term effects of developmental exposure to a glyphosate-based herbicide (GBH) by analyzing serum melatonin levels and cellular changes in the striatum of adult male rats (90 days old). Pregnant and lactating rats were exposed to 3% GBH (0.36% glyphosate) through drinking water from gestational day 5 to postnatal day 15. The offspring showed reduced serum melatonin levels (43%) at the adult age compared with the control group. The perinatal exposure to GBH also induced long-term oxidative stress-related changes in the striatum demonstrated by increased lipid peroxidation (45%) and DNA/RNA oxidation (39%) together with increased protein levels of the antioxidant enzymes, superoxide dismutase (SOD1, 24%), glutamate-cysteine ligase (GCLC, 58%), and glutathione peroxidase 1 (GPx1, 31%). Moreover, perinatal GBH exposure significantly increased the total number of neurons (20%) and tyrosine hydroxylase (TH)-positive neurons (38%) in the adult striatum. Mechanistic in vitro studies with primary rat pinealocytes exposed to 50 µM glyphosate demonstrated a decreased melatonin secretion partially through activation of metabotropic glutamate receptor 3 (mGluR3), while higher glyphosate levels (100 or 500 µM) also reduced the pinealocyte viability. Since decreased levels of the important antioxidant and neuroprotector melatonin have been associated with an increased risk of developing neurodegenerative disorders, this demonstrates the need to consider the melatonin hormone system as a central endocrine-related target of glyphosate and other environmental contaminants.

Perinatal Exposure to an Environmentally Relevant Mixture of Phthalates Results in a Lower Number of Neurons and Synapses in the Medial Prefrontal Cortex and Decreased Cognitive Flexibility in Adult Male and Female Rats

The growth and organization of the developing brain are known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, such as mPFC. This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 μg/kg/d through pregnancy and for 10 d while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.SIGNIFICANCE STATEMENT Humans globally are exposed on a daily basis to a variety of phthalates, which are endocrine-disrupting chemicals. The effects of phthalate exposure on the developing brain, especially on cognitively relevant regions, such as the mPFC, are not known. Here, we use a rat model of human prenatal exposure to an environmentally relevant mixture of phthalates and find that there is an appreciable reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. These results may have serious implications for humans given that the mPFC is involved in executive functions and is implicated in the pathology of many neuropsychiatric disorders.

Long-term effects of perinatal exposure to low doses of cadmium on the prostate of adult male rats.

Developmental toxicity caused by environmental exposure to heavy metals during the perinatal period has raised questions about offspring health. Cadmium (Cd) is an endocrine-disrupting chemical with the potential to interfere with morphogenesis and susceptibility to diseases in reproductive organs. Taking into account that in the rat prostate morphogenesis occurs during the perinatal period, and that pregnant females absorb and retain more dietary Cd than their non-pregnant counterparts, it is important to understand the effects of perinatal Cd exposure on the adult rat prostate. Therefore this study investigated the effects of gestational and lactational Cd exposure on adult offspring rat prostate histopathology. Pregnant rats (n=20) were divided into two groups: Control (treated with aqueous solution of sodium acetate 10mg/l) and treated (treated with aqueous solution of cadmium acetate 10mg/l) administered in the drinking water. After weaning, male offspring from different litters (n=10) received food and water 'adlibitum'. The animals were euthanized at postnatal day 90 (PND90), the ventral prostates (VPs) were removed, weighed and examined histopathologically. Blood was collected for the measurement of testosterone (T) levels. Immunohistochemistry for androgen receptor (AR) and Ki67, and a TUNEL assay were performed. There were no differences in T levels, cell proliferation and apoptosis indexes, or AR immunostaining between the experimental groups. Stromal inflammatory foci and multifocal inflammation increased significantly in the treated group. These changes were associated with inflammatory reactive epithelial atypia and stromal fibrillar rearrangement. In conclusion, VP was permanently affected by perinatal Cd exposition, with increased incidence of inflammatory disorders with ageing.

Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases-an Overview of Experimental Studies.

The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies.

Altered profiles of spontaneous novelty seeking, impulsive behavior, and response to D-amphetamine in rats perinatally exposed to bisphenol A.

Bisphenol A (BPA) is an environmental estrogen with potentially averse effects on public health. We studied the long-term effects of perinatal exposure to BPA on later behavior in adult rats of both sexes. BPA or vehicle was administered orally to mother rats from mating to pups' weaning, at a concentration (0.040 mg/kg) within the range of human exposure. The offspring of both sexes were tested at adolescence (postnatal days 35-45) for novelty preference (experiment 1). After a 3-day familiarization to one side of a two-chamber apparatus, on day 4 rats were allowed to freely explore the whole apparatus. BPA-exposed females spent significantly less time than did controls in exploration of the novel side (i.e., increased neophobia), whereas no effect was found in the male group. At adulthood, the same animals were food deprived and tested for profiles of impulsive behavior (experiment 2), in operant chambers provided with two nose-poking holes (delivering either five or one food pellet). After the establishment of a baseline preference for the large reinforcer, a delay was introduced before the delivery of the five food pellets, which was progressively increased each day (10, 20, 30, 45, 60, 80, 100 sec). As expected, all animals exhibited a progressive shift toward the immediate but smaller reinforcer. A reduced level of impulsive behavior (i.e., a shift to the right in the intolerance-delay curve) was evidenced in BPA-treated rats. The frequency of inadequate responding (during the length of the delay) also provided a measure of restless behavior. Interestingly, the profile of BPA-treated males was feminized, strongly resembling that of control females. Animals were then tested (experiment 3) for the response to an amphetamine challenge (1 mg/kg, subcutaneously). The drug-induced increment activity was significantly less marked in BPA-treated male rats compared with controls. These findings provide clear indirect evidence of long-term alterations in brain monoaminergic function after perinatal BPA exposure. This may be a cause for concern for public health, confirming that exposure to a weak environmental estrogen in the period of sexual differentiation of the brain can influence adult behavior.

Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins

Polychlorinated biphenyl's (PCBs) and dioxins are environmental pollutants. Calculated on a body weight basis, prenatally as well as postnatally through breast‐feeding, large amounts are transferred from mother to the child. Formula is free of these substances. Considering their potential developmental neurotoxicity, we investigated long‐term effects of perinatal exposure to PCBs and dioxins on neurological and cognitive development. Methods. A group of 418 infants were followed from birth up to 6 years of age. Half of them were fully breast fed (BF) for at least 6 weeks. Prenatal PCB exposure was measured from cord and maternal blood. Postnatal exposure was reflected by PCB and dioxin levels in breast and formula milk and plasma PCB concentrations at 42 months of age. Both neurological and cognitive development were taken as outcome variables at 18, 42 months and at 6 years of age. At 18 and 42 months neurological condition was evaluated according to Hempel and Touwen and at 6 years of age according to Touwen. Condition was evaluated in terms of optimality. Separately, the fluency of movements was scored. Cognitive abilities were measured at 18 months by means of the Bayley Scales of Infant Development, at 42 months of age by the Kaufman Assessment Battery for Children (K‐ABC) and at 6 years of age by the McCarthy Scales. Results. At 18 months of age cognitive development was not affected by either pre‐ or postnatal exposure to the measured PCBs and dioxins. However, neurological examination showed an adverse effect of prenatal exposure to the measured pollutants on the neurological optimality score. At 42 months of age we found negative associations between prenatal PCB exposure and cognitive development. However, no effect was demonstrated of postnatal exposure to the measured pollutants. Neurological development was not affected by either pre‐ or postnatal exposure to PCBs and dioxins. At 6 years of age the preliminary results showed no evidence that cognitive and neurological development are affected by pre‐ and postnatal exposure to these pollutants. Despite a higher PCB exposure from breast milk we found at 18 months, 42 months of age, and at 6 years of age a beneficial effect of breast feeding on the quality of movements, in terms of fluency. Conclusion. These data support the evidence obtained from similar studies in the USA that prenatal exposure to PCBs may have subtle negative effects on early neurological and cognitive development of the child. Further studies are required to evaluate these findings in other parts of the world. Our studies showed consistently a beneficial effect of breast‐feeding on brain development from 18 months up to school age.

Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice.

The new antiretroviral treatments that combine the zidovudine (AZT) regimen with lamivudine (3TC) appear as a cost-effective alternative to the current AZT monotherapy to prevent mother-to-fetus transmission of the HIV-1 virus. Recent evidence in uninfected children raised concern about the long-term effects of perinatal exposure to AZT and 3TC, especially when used in combination. Animal studies indicated behavioral changes in offspring exposed perinatally to both AZT and 3TC, whereas no animal data are available on the effects of the perinatal exposure to the AZT + 3TC combination on neurodevelopment. Pregnant CD-1 mice received p.o. AZT + 3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) twice daily from gestational day 10 to delivery. Maternal reproductive endpoints such as pregnancy length, abortion, litter size, sex ratio, and offspring viability were assessed. Pups were scored for different somatic and behavioral endpoints, including sensorimotor development, homing performance on postnatal day (PND) 10, passive-avoidance testing (PND 22-23), locomotor activity (PND 23), and social interaction (PND 35). While no effects were observed on maternal reproductive endpoints, treated pups showed a long-lasting reduction of body weight and a slightly delayed maturation of placing and grasping reflexes and pole grasping. No effects on passive-avoidance or locomotor activity were found. AZT + 3TC-treated mice showed selective alterations in the social interaction test; the treated female offspring also displayed a significant reduction of affiliative interactions. The combination of AZT and 3TC (1) induced small, but more marked, effects on somatic and sensorimotor development than either of these drugs administered separately; and (2) affected juvenile social behavior.

Long-term effects of perinatal exposure to 5 alpha-dihydrotestosterone on normal and neoplastic mammary development in mice.

Daily subcutaneous injection of 200 microgram 5 alpha-dihydrotestosterone to SHN female mice for the first 5 days of postnatal life resulted in the stimulation of normal and neoplastic mammary development at advanced ages and it also induced the ovarian anovulatory syndrome and stimulated pituitary prolactin secretion. Daily subcutaneous injections of 1 mg 5 alpha-dihydrotestosterone to pregnant mice from day 12 to day 15 of pregnancy (prenatal treatment) had no effects on their offspring. Long-term effects of 5 alpha-DHT on normal and neoplastic mammary development in mice were generally not so marked as those observed previously with 5 beta-dihydrotestosterone which is biologically inactive in the adult.

Long-term effects of progesterone or diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice

The long-term effects of perinatal exposure to progesterone or diethylstilbestrol (DES) with or without the additional administration of estradiol benzoate (EB) on mammary tumorigenesis were studied in virgin SLN mice bearing expressed mammary tumor virus. Spontaneous mammary tumorigenesis of female offsprings from mothers receiving single subcutaneous injections of DES ( 5 μ g) on day 12 of pregnancy (prenatal 12 days) was significantly lower than that of offsprings from mothers given progesterone ( 1 mg) or oil on the same day. This difference in mammary tumorigenesis was not altered by the s.c. EB implantation during 3 months between 2 and 5 months of age. Single injection of progesterone at prenatal 17 days with or without EB after maturity also inhibited mammary tumorigenesis at advanced ages. Mammary tumorigenesis was enhanced by s.c. injection of progesterone ( 100 μ g) or DES ( 0.1 μ g) on the day of birth; however, it was arrested by EB after maturity. All findings indicate that long-term effects of perinatal exposure to steroids or DES on mammary tumorigenesis at advanced ages are largely dependent upon perinatal ages of the subjects and that sex hormones given after maturity can modulate these perinatal hormone effects.

The influence of prenatal or neonatal administration of 2-bromo-alpha-ergocryptine on pituitary prolactin secretion and normal and neoplastic mammary growth in adult mice.

In view of the clinical use of 2-bromo-alpha-ergocryptine (CB-154) during pregnancy, longterm effects of perinatal exposure to this drug on pituitary prolactin secretion and mammary tumorigenesis were studied experimentally using a high mammary tumor strain of SHN female mice. Pregnant mice were given daily subcutaneous injections of 0.3 mg CB-154 for 4 days from day 12 to day 15 of pregnancy (prenatal treatment). Another group of mice received daily dose of 0.06 mg CB-154 for the first 5 days of postnatal life (neonatal treatment). Either prenatal or neonatal treatment with CB-154 resulted in little alteration of the pattern of estrous cycle, ovarian structure and pituitary and plasma levels of prolactin. There was no difference between the control and mice treated neonatally with CB-154 in mammary tumorigenesis. On the other hand, somewhat delayed mammary tumor appearance was observed in mice treated prenatally with CB-154. These findings postulate that there is little deleterious influence of perinatal exposure to CB-154 on pituitary-ovary-mammary gland systems at advanced ages.