Search

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks’ gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p< 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q< 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3–43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8–66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS’ influence on pregnancy outcomes.

Phthalates are synthetic chemicals widely used in consumer products and have been identified to contribute to preterm birth. Existing studies have methodological limitations and potential effects of di-2-ethylhexyl phthalate (DEHP) replacements are poorly characterised. Attributable fractions and costs have not been quantified, limiting the ability to weigh trade-offs involved in ongoing use. We aimed to leverage a large, diverse US cohort to study associations of phthalate metabolites with birthweight and gestational age, and estimate attributable adverse birth outcomes and associated costs.

Estrogens have been shown to both enhance and impair cognitive function depending on several factors, including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2 [+ or -] 8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol-treated rats showed a lower ratio of reinforced to nonreinforced presses. These data suggest that chronic estrogen exposure may impair rats' abilities on measures of executive function including working memory and response inhibition. Keywords: estrogen, cognition, aging, DSA, DRL

Blood samples were collected from 28 mothers and from 38 school-aged children from Michigan farms on which there were polychlorinated biphenyl (PCB)-contaminated silos. The samples were analyzed for PCBs and other contaminants, including polybrominated biphenyis (PBBS) and dichlorodiphenyl trichloroethane (p,p'-DDT + p,p'-DDE) via packed column gas chromatography. The PCBs were quantified, using the Webb-McCall method, with Aroclors 1016 and 1260 used as reference standards. Approximately 42% of the children had serum PCB levels above the detection limit of 3.0 ng/ml. The values ranged from 3.1 to 23.3 ng/ml, with a mean of 6.8 ng/ml. In contrast, PCBs were detected in 86% of the mothers. The mean serum concentration was somewhat higher for the mothers (9.6 ng/ml), but the range was similar to that found for the children. PBBs were not detected in any of the children, but were present in trace amounts in 25% of the mothers. Conversely, DDT was present in 66% of the children and 93% of the mothers. As with PCBs, DDT concentrations were somewhat higher in the mothers. DDE accounted for 89% of the total DDT in serum. Various potential sources of exposure were evaluated as possible determinants of serum PCB levels, using hierarchical multiple regression. Years of residence on a silo farm and consumption of PCB-contaminated Great Lakes fish both accounted for significant portions of the variance in maternal serum PCB levels. Exposure via breast-feeding explained a large and highly significant proportion of the variance in the children's serum PCB concentrations, suggesting that breast milk was the primary source of PCB exposure for these children. Years of residence on a silo farm also explained a significant proportion of the variance in children's serum PCBs. The pattern of Webb-McCall elution peaks was similar in the children and mothers and closely resembled patterns observed in other Michigan cohorts exposed to PCBs through consumption of PCB-contaminated Great Lakes fish.

•Multiple aspects of infant cognition were evaluated using infrared eye tracking.•Prenatal phthalate exposure was associated with slower information processing.•But associations were only in males or infants who saw a particular stimulus set.•Prenatal phthalate exposure may also be associated with poorer recognition memory.

The Healthy Eating Index (HEI)-2015 and Alternative Healthy Eating Index (AHEI)-2010 evaluate diet holistically in pregnancy. However, it remains unclear how individual index components interact to contribute to health.

Estrogens are well known for their enhancing effects on hippocampus-sensitive cognition. However, estrogens can also impair learning and memory, particularly the acquisition of striatum-sensitive tasks. These cognitive shifts appear to be mediated through local estrogen receptor (ER) activation in each neural structure, but little information is known regarding which specific ER subtypes drive the opposing effects on learning. Elucidating the mnemonic roles of discrete ER subtypes is essential for predicting how treatments with distinct ER pharmacology such as drugs, hormone therapies, and phytoestrogen supplements affect cognitive abilities in and thus the daily lives of the women who take them. The present study examined the effects of the ERα-selective compound propyl pyrazole triol and the ERβ-selective compounds diarylpropionitrile and Br-ERb-041 on place and response learning in young adult female rats. Long-Evans rats were ovariectomized and maintained on phytoestrogen-free chow for 3 weeks before behavioral training, with treatments administered via subcutaneous injection 48 and 24 hours before testing. A dose-response paradigm was used, with each compound tested at 4 different doses in separate groups of rats. Propyl pyrazole triol, diarylpropionitrile, and Br-ERb-041 all enhanced place learning and impaired response learning, albeit with distinct dose-response patterns for each compound and task. These results are consistent with the detection of ERα and ERβ in the hippocampus and striatum and suggest that learning is modulated via activation of either ER subtype.

Estrogen deficiency after menopause results in rapid bone loss, predisposing women to osteoporotic fractures. Genistein, a phytoestrogen present in high concentrations in soy, is an ingredient in dietary supplements aggressively marketed for bone health. However, in a recent long-duration clinical trial in postmenopausal women, the efficacy of soy extracts in reducing bone loss was disappointing. To better understand the failure of soy extracts to consistently induce a robust skeletal response in women, we investigated the long-term (5 mo) efficacy of genistein, administered as a daily oral supplement, (1) in preventing cancellous bone loss in skeletally mature virgin Long-Evans rats ovariectomized at 7 months of age and (2) in improving cancellous bone mass and architecture in aged retired-breeder rats ovariectomized at 16 or 22 months of age.

Soy-based infant formulas are widely used in the United States and some other countries. These formulas contain high levels of the estrogenic isoflavone genistein, leading to concern that neonatal genistein exposure could cause acute and/or long-term adverse effects on reproductive and other organs. However, previous work to assess genistein effects in rodent models has not typically replicated the route of delivery and/or serum genistein concentrations reported for soy formula-fed human infants. Our objective was to develop a mouse model that more closely mimics the oral genistein exposure and total serum genistein concentrations observed in soy formula-fed infants. Mouse pups were dosed orally with genistein in a soy formula-corn oil emulsion from Postnatal Day (PND) 1 to PND 5, then effects on reproductive and nonreproductive organs were assessed after dosing and during subsequent development. Neonatal treatment resulted in changes both at the completion of dosing (PND 5) and in adult animals. At PND 5, neonatal genistein treatment caused increased relative uterine weight and down-regulation of progesterone receptor in uterine epithelia. Estrogenic effects of genistein were also seen in the neonatal ovary and thymus, which had an increase in the incidence of multioocyte follicles (MOFs) and a decrease in thymic weight relative to body weight, respectively. The increased incidence of MOFs persisted into adulthood for neonatally treated genistein females, and estrous cycle abnormalities were seen at 6 mo of age despite normal fertility in these mice. The immediate and long-term effects in this neonatal animal model raise concerns that high serum concentrations of genistein are estrogenic and could potentially impact the development of human infants fed soy formula.

Due to the estrogenic properties of soy-derived isoflavones, many postmenopausal women are using these compounds as a natural alternative to hormone replacement therapy (HRT). How isoflavones impact breast cancer in postmenopausal women is important, because a majority of breast cancer cases occur in this age group. Chemical induction of mammary tumors in female rats has been used to determine that exposure of the mammary gland to soy isoflavones prior to tumor induction is protective against tumor formation. Here we investigate the effect of dietary genistein on mammary tumors that have already formed. The study was designed to determine the action of dietary genistein in a low endogenous estrogen environment as is observed in postmenopausal women. Animals were ovariectomized (OVX) after mammary tumor development and were then placed into one of three treatment groups: positive-control (OVX+ estradiol implant), genistein (OVX+ 750 p.p.m. genistein) and negative-control (OVX alone). Tumors were distinguished as malignant or benign by histopathological examination and were further characterized as either estrogen-dependent or estrogen-independent using immunohistochemistry to identify the presence of both estrogen receptor (ER) α and the progesterone receptor (PR). Genistein at 750 p.p.m. increased the weight of estrogen-dependent adenocarcinomas in ovariectomized rats compared with the negative-control animals. Genistein treatment also resulted in a higher percentage of proliferative cells in tumors and increased uterine weights when compared with negative-control animals. Collectively, these effects are probably due to the estrogenic activity of genistein. Plasma genistein concentrations in animals fed the isoflavone-containing diet were at physiological levels relevant to human exposure. Estradiol concentrations in ovariectomized animals not receiving an estradiol supplement were similar to those observed in postmenopausal women. The data suggest that in an endogenous estrogen environment similar to that of a postmenopausal woman, dietary genistein can stimulate the growth of a mammary carcinogen MNU-induced estrogen-dependent mammary tumors.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been associated with cognitive deficits in children exposed in utero.Cognitive deficits due to PCB exposure have also been documented in animal models, but the underlying behavioral mechanisms responsible for those deficits remain to be elucidated. The current study examined the effects of gestational and lactational exposure to PCBs on spatial discrimination–reversal learning (spatial RL) in rats using standard two-lever operant testing chambers. Pregnant Long–Evans rats (10/dose) received either 0 or 6 mg/kg Aroclor 1254 (A1254) po in corn oil from gestational day 6 to postnatal day 21. One male and one female from each litter were tested on spatial RL beginning at 190–220 days of age. Animals were reinforced with a 45-mg food pellet for pressing the lever associated with the correct spatial location (either left or right). After reaching 85% correct performance for 2 consecutive days, the opposite spatial location was reinforced. Five of these position reversals were given. Male rats exposed to A1254 made significantly more total errors (121.6 ± 12.5) on the first reversal than controls (90.7 ± 5.8). In contrast, female rats exposed to A1254 exhibited deficits on the fourth and fifth reversals (23.6 ± 4.2, 17.0 ± 2.8 and 36.7 ± 4.7, 26.8 ± 2.5 for control and exposed animals, respectively). Response-pattern analyses in the A1254-exposed male and female rats revealed fundamental differences in the underlying behavioral mechanisms responsible for the deficits. A1254-exposed males exhibited an increased tendency to incorrectly respond to the previously correct stimulus (i.e., perseverate) following a reversal while A1254-exposed females exhibited impairments in their ability to make new associations with a reinforced spatial location (i.e., associative deficit). These data provide new insights into the underlying behavioral mechanisms that may be responsible for the spatial learning deficits observed in PCB-exposed rodents and monkeys.

Recently we reported that in uteroand lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or coplanar polychlorinated biphenyls (PCBs) resulted in a reduction of errors on a radial arm maze (RAM) working memory task. The effect was more pronounced in males than in females. In this study, we further investigated the effects of in utero and lactational exposure to TCDD on learning and memory by testing male and female TCDD-exposed rats on three different spatial learning and memory tasks: the RAM, the Morris water maze (MWM), and spatial discrimination-reversal learning (RL), as well as on a nonspatial learning task, visual RL. Time-mated Sprague–Dawley rats were gavaged with either TCDD (0.1 μg/kg/day) or corn oil vehicle on gestation days 10–16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on the same RAM working memory task used in the previous study. Again, the TCDD-exposed male rats displayed a pronounced decrease in errors relative to control males. Following the RAM testing, the same animals were tested on the MWM, but no differences between the exposed and control rats were observed. Another male and female from each litter were tested on spatial RL on a T-maze. There were no differences between the exposed and control rats on this task. Following spatial RL, the same rats were tested on visual RL on the same maze. The exposed animals did not differ from controls on original learning, but took more trials to reach criterion on the first and second reversals. These results demonstrate a reliable, but task-specific, facilitation of spatial learning and memory in male rats exposed to TCDD during gestation and lactation. In contrast, both male and female TCDD-exposed rats showed a deficit in learning on the visual RL task. This pattern is consistent with that seen in earlier monkey studies. Perinatally TCDD-exposed monkeys were facilitated on certain spatial tasks, but impaired on visual RL tasks.

Exposure to contaminants in Great Lakes fish has been linked to impaired neuropsychological functioning in children, but neurological function of exposed adults has not been evaluated. This report describes a cross-sectional analysis of the effects of PCB/DDE exposure from contaminated fish on fine motor function in older adults. The subjects were 50–90-year-old Michigan residents who were members of a previously established study cohort. Fisheaters ate 24 lbs or more of sport-caught Lake Michigan fish/year at the time they were originally recruited in 1980–1982. Age- and sex-matched non-fisheaters ate 6 or fewer lbs/year. Outcome measures were scores on the Static Motor Steadiness Test (SMST) and Grooved Pegboard Test (GPT). PCB/DDE exposure was determined through serum analyses performed at the time of recruitment into the present study in 1993–1995. Because of the high correlation between serum PCB and DDE levels in this sample (Spearmanr=0.64,P<0.0001), the effects of the two contaminants were assessed jointly using a single derived exposure variable=Low=both PCB and DDE at or below the medians of their respective distributions, intermediate=PCB and/or DDE in the third quartile, and high=PCB and/or DDE in the upper quartile. In unadjusted analyses, high exposure to PCBs/DDE was associated with significantly poorer performance on the GPT (P=0.03). However, in the multiple regression model, age and gender emerged as the most significant factors affecting GPT scores, and exposure to PCB/DDE was not significant. Performance on the SMST was not related to PCB/DDE exposure in initial unadjusted analyses, but performance with the dominant hand was marginally (P=0.052) associated with exposure in the final model. Scores on the SMST improved slightly as PCB/DDE exposure increased. A similar trend was not observed for the nondominant hand (P=0.46). These findings suggest that PCB/DDE exposure from Great Lakes fish has not significantly impaired hand steadiness or visual-motor coordination in this sample of older adults.

Monkeys exposed to low, chronic levels of polychlorinated biphenyls (PCBs) in utero and during nursing until 4 months after birth were tested at 4–6 years of age on delayed spatial alternation (DSA), a spatial learning and memory task. Deficits in performance accuracy were detected in two cohorts of monkeys whose mothers had been fed 2.5 ppm of the PCB mixture, Aroclor 1248, in their diet for an 18-month period ending at least 12 months prior to pregnancy. The deficit was most apparent at the shorter delays, suggesting that it was not due to memory impairment, but may have been due to impairments in associational or attentional processes. There may also have been a deficit in a group of monkeys whose mothers were fed 1.0 ppm of the PCB mixture, Aroclor 1016. However, the deficit in this group was less pronounced than in the other groups. The appearance of a PCB-induced cognitive deficit more than 3 years after the end of exposure indicated the existence of very long-term adverse consequences of low-level perinatal PCB exposure.

Spatial Learning Deficits in Adult Rats Exposed to ortho-Substituted PCB Congeners during Gestation and Lactation. Schantz, S. L., Moshtaghian, J., and Ness, D. K. (1995). Fundam. Appl. Toxicol.26, 117-126.

Recently we reported that in utero and lactational exposure to specific ortho-substituted polychlorinated biphenyl (PCB) congeners resulted in a learning deficit on a delayed spatial alternation (DSA) task in female rats. In this study, spatial learning and memory was assessed following in utero and lactational exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Time-mated Sprague-Dawley rats were dosed with PCB 77 (3,3′,4,4′-tetrachlorobiphenyl), 2 or 8 mg/kg/day; PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), 0.25 or 1.0 μg/kg/day; TCDD, 0.025 or 0.1 μg/kg/day; or corn oil vehicle via gavage on gestation days 10–16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on an eight-arm radial maze working memory task. The TCDD-exposed rats displayed pronounced decreases in errors relative to controls. PCB 77- and PCB 126-exposed rats showed similar, but less pronounced, decreases in errors. The same animals were later tested on a T-maze DSA task, but no differences among groups were observed. In conclusion, perinatal exposure to low doses of TCDD or structurally related coplanar PCBs appeared to facilitate acquisition of a working memory task on the radial arm maze. This effect was very different from that previously observed in rats exposed to ortho-substituted PCB congeners. The rats exposed to ortho-substituted PCBs did not differ from controls on the radial arm maze and were impaired on the T-maze DSA task. Together these findings suggest that coplanar and ortho-substituted PCBs may have different mechanisms of action on the CNS.

The potential neurotoxicity of PCBs was first recognized in 1968 when a number of Japanese people became ill after ingesting rice oil that was contaminated with PCBs during the manufacturing process (Yusho). Later a similar exposure occurred in Taiwan (YuCheng). Children born to Taiwanese mothers who consumed PCB-contaminated rice oil were followed and a number of developmental abnormalities, including lower body weight and height, higher activity levels, greater incidence of behavior problems, and lower IQ scores, were observed. However, interpretation of these findings is complicated by the fact that there did not appear to be any relationship between available indices of exposure and severity of effects, and by the fact that the PCBs to which the Taiwanese were exposed contained unusually high concentrations of dibenzofurans, which are many times more toxic than PCBs, and may have been responsible for some or all of the observed effects. Since the Yusho and YuCheng episodes, several studies have been initiated to study the neurobehavioral effects of exposure to the lower levels of PCBs present in the environment. The two studies published to date have yielded conflicting results. Jacobson, Jacobson, and colleagues reported that in utero PCB exposure was associated with decreased birth weight and head circumference, shorter gestation, and several adverse outcomes on the Brazelton Neonatal Assessment Battery. Later they reported that the body weight deficits associated with prenatal PCB exposure were still present at 5 months and 4 years of age. Deficits in memory function were observed at 7 months and 4 years. Rogan, Gladen, and colleagues did not find any evidence of decreased birth weight or head circumference. Nor did they find any evidence of deficits in memory function. However, they did observe some similar effects on the Brazelton Neonatal Assessment Battery. They also observed a small delay in psychomotor development in the most highly PCB-exposed children, but the effect did not persist beyond 2 years of age. A number of methodological concerns have been raised about the Jacobson study, including issues related to exposure assessment, sample selection, and control of potential confounding variables. However, it is not clear that these shortcomings can explain the discrepancies between their findings and those of Rogan and Gladen. Other possible explanations include differences in exposure levels or PCB congener patterns between the two cohorts, differences in sociodemographic variables between the two cohorts, or other problems inherent in trying to detect subtle neuropsychological deficits at exposure levels that are near the threshold for effects. Hopefully, several new studies that are currently underway will help to resolve the uncertainties regarding the risks of perinatal PCB exposure that have been created by the conflicting results of these early studies.

Because of the decline in central nervous system function that occurs with age, older people may be at greater risk of neurological dysfunction following exposure to neurotoxic contaminants in the environment. This study wasdesigned to assess the neuropsychological functioning of a group of 50-90- year-old fisheaters exposed to polychlorinated biphenyls (PCBs) through Great Lakes fish consumption, and a group of age- and sex-matched nonfisheaters selectedfrom the Michigan Department of Public Health's established cohort of fisheaters and nonfisheaters. A neuropsychological assessment battery, demographic interview, and fish consumption questionnaire were developed and piloted on similarly aged men and women in the Lansing and Detroit, Michigan, areas. The assessment battery included tests of motor function, memory and learning, executive functions, and visual-spatial functions, and took approximately two hours to administer. Most of the tests included in the battery have been shown to be sensitive to subtle, age-related declines in cognitive and motor function. The demographic questionnaire included questions on a number of important control variables that could influence the neuropsychological end points that were assessed in the study. These included demographic background, alcohol consumption, tobacco use, prescription and nonprescription drug use, medical history (including psychiatric illnesses), employment history, and activity level. The fish consumption questionnaire asked about historical and current consumption of specific fish species from each of the Great Lakes and its tributaries and was based on the fish consumption advisories published in the 1992 Michigan Fishing Guide. The questionnaire also asked about consumption of wild game, fish preparation and cooking methods, serving size, and changes in fish consumption patterns over time. After each subject completed the neuropsychological assessment, demographic interview, and fish consumption questionnaire, a blood sample was collected for analysis of PCBs, dichloro diphenyl dichloroethene (DDE), and ten other contaminants frequently detected in Great Lakes fish. Subject recruitment for the study began in July 1993 and was completed in November 1995. The data will be analyzed in two steps: first, to assess differences in confounding variables between fisheaters and nonfisheaters; and secondly, to determine the independent effects of Great Lakes fish consumption, as well as serum PCB and DDE levels, on cognitive and motor function after controlling for all identified covariates. Three indices of PCB exposure—total PCBs, total ortho-substituted PCBs and total coplanar PCBs—will be assessed. These studies should shed light on three questions: 1) Does consumption of contaminated fish from the Great Lakes exacerbate or accelerate the normal age-related decline in cognitive and motor function? 2) Do serum PCB or DDE concentrations predict the degree of behavioral dysfunction? and 3) If PCB exposure is related to behavioral outcomes, which class of PCB congeners, ortho-substituted or coplanar, are responsible for the cognitive and motor deficits?

Polychlorinated biphenyls (PCBs) and dioxins are widespread environmental contaminants that are suspected of causing cognitive deficits in children exposed in utero. Very little is known about which of the PCB and dioxin congeners present in the environment are responsible for the changes in cognitive function or about the mechanisms through which these chemicals affect the central nervous system (CNS). Because both PCBs and dioxins reduce circulating thyroid hormone levels, it has been proposed that these chemicals may affect CNS function indirectly by reducing the availability of thyroid hormone to the brain during development. Thyroid hormones play a critical role in brain development, and spatial learning and memory is one of the behavioral functions most severely affected by neonatal hypothyroidism. In the studies reviewed here, we investigated the effects of three ortho-substituted PCBs, two coplanar PCBs and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on spatial learning and memory in the rat. Pups exposed to PCBs or TCDD in utero and during lactation were tested when they reached adulthood. All three ortho-substituted PCBs caused deficits in spatial learning, but only two of the three reduced circulating thyroid hormone concentrations. Furthermore, the learning deficit was observed only in females, but thyroid hormones were equally depressed in males and females. Thus, the PCB-induced deficit in spatial learning did not appear to be mediated by the decreased thyroid hormone levels. TCDD and coplanar PCBs caused moderate reductions in thyroid hormone, but facilitated rather than impaired spatial learning, an effect that has been reported in neonatally hyperthyroid rats. The possibility that TCDD and coplanar PCBs may act as “mixed” thyroid agonists/antagonists causing hypothyroid-like effects in some tissues and hyperthyroid-like effects in other tissues is discussed.