•Prenatal exposure to MnBP was related to lower testosterone in 3–4 months old boys.•Maternal phthalate exposure was related to lower T/LH ratio in 3–4 months old boys.•Anti-androgenic phthalates may ...affect mini-puberty occurring at 3–4 months of age.
Phthalates are plastic softeners with anti-androgenic properties. Prenatal exposure has led to lower testosterone (T) levels and smaller testicles in adult rats. To our knowledge, no studies have examined associations between prenatal phthalate exposure and sex hormone concentrations in infants.
To study associations between phthalate exposure in Danish pregnant women and T, luteinizing hormone (LH), follicle stimulating hormone (FSH), Δ4-androstenedione (adion), 17α-hydroxyprogesterone (17-OHP) dehydroepiandrosterone sulfate (DHEAS) concentrations in their infants (N = 479) during mini-puberty.
Concentrations of 12 phthalate metabolites from six phthalate diesters were measured in urine samples collected from 2010 to 2012 from 479 pregnant women participating in the Odense Child Cohort at gestational week 28 (range 20.4–30.4). Serum T, LH, FSH, adion, 17-OHP, DHEAS, weight and height were measured approximately three months after expected date of birth. Associations between prenatal phthalate exposure and gonadotropin and androgen metabolite concentrations were estimated in boys and girls separately in adjusted linear regression models.
T concentration was lower in boys prenatally exposed to phthalates. Maternal urinary concentrations of summed mono-iso-butyl and mono-n-butyl phthalate (∑MBPi+n) and summed metabolites of di-iso-nonyl phthalate (∑DiNPm) were associated with lower T/LH ratio in male offspring and a dose-response association was found. FSH was 14% (95% CI: 1; 25) lower among male offspring from mothers exposed to ∑DiNPm in the highest compared to the lowest tertile. No association was found for girls.
Even in these low exposed children, we found a significant decrease in T/LH ratio during mini-puberty in boys prenatally exposed to phthalates, which may suggest impairment of Leydig cells. The children will be followed as they approach adrenarche and pubarche in order to assess if long-term adverse effects persist.
Bisphenol A (BPA) is a non-persistent chemical with endocrine disrupting abilities used in a variety of consumer products. Fetal exposure to BPA is of concern due to the elevated sensitivity, which ...particularly relates to the developing brain. Several epidemiological studies have investigated the association between prenatal BPA exposure and neurodevelopment, but the results have been inconclusive.
To assess the association between in utero exposure to BPA and Attention Deficit/Hyperactivity Disorder (ADHD-) symptoms and symptoms of Autism Spectrum Disorder (ASD) in 2 and 5-year old Danish children.
In the prospective Odense Child Cohort, BPA was measured in urine samples collected in gestational week 28 and adjusted for osmolality. ADHD and ASD symptoms were assessed with the use of the ADHD scale and ASD scale, respectively, derived from the Child Behaviour Checklist preschool version (CBCL/1½-5) at ages 2 and 5 years. Negative binomial and multiple logistic regression analyses were performed to investigate the association between maternal BPA exposure (continuous ln-transformed or divided into tertiles) and the relative differences in ADHD and ASD problem scores and the odds (OR) of an ADHD and autism score above the 75th percentile adjusting for maternal educational level, maternal age, pre-pregnancy BMI, parity and child age at evaluation in 658 mother-child pairs at 2 years of age for ASD-score, and 427 mother-child pairs at 5 years of age for ADHD and ASD-score.
BPA was detected in 85.3% of maternal urine samples even though the exposure level was low (median 1.2 ng/mL). No associations between maternal BPA exposure and ASD at age 2 years or ADHD at age 5 years were found. Trends of elevated Odds Ratios (ORs) were seen among 5 year old children within the 3rd tertile of BPA exposure with an ASD-score above the 75th percentile (OR = 1.80, 95% CI 0.97,3.32), being stronger for girls (OR = 3.17, 95% CI 1.85,9.28). A dose-response relationship was observed between BPA exposure and ASD-score at 5 years of age (p-trend 0.06) in both boys and girls, but only significant in girls (p-trend 0.03).
Our findings suggest that prenatal BPA exposure even in low concentrations may increase the risk of ASD symptoms which may predict later social abilities. It is therefore important to follow-up these children at older ages, measure their own BPA exposure, and determine if the observed associations persist.
•Human exposure to chemical cocktails demands new technologies to assess this combined exposure.•Receptor-based in vitro assays can be used as biomarkers of effect in human tissue.•In vitro ...biomarkers of effect take mixture effects of chemicals into account.•AhR, ER and AR activities have been linked to various disease outcomes in humans.•The potential of true effect-directed analysis on human tissues remains to be explored.
Humans are exposed to a large number of chemicals from sources such as the environment, food, and consumer products. There is growing concern that human exposure to chemical mixtures, especially during critical periods of development, increases the risk of adverse health effects in newborns or later in life. Historically, the one-chemical-at-a-time approach has been applied both for exposure assessment and hazard characterisation, leading to insufficient knowledge about human health effects caused by exposure to mixtures of chemicals that have the same target. To circumvent this challenge researchers can apply in vitro assays to analyse both exposure to and human health effects of chemical mixtures in biological samples. The advantages of using in vitro assays are: (i) that an integrated effect is measured, taking combined mixture effects into account and (ii) that in vitro assays can reduce complexity in identification of Chemicals of Emerging Concern (CECs) in human tissues.
We have reviewed the state-of-the-art on the use of receptor-based in vitro assays to assess human exposure to chemical mixtures and related health impacts. A total of 43 studies were identified, in which endpoints for the arylhydrocarbon receptor (AhR), the estrogen receptor (ER), and the androgen receptor (AR) were used. The majority of studies reported biological activities that could be associated with breast cancer incidence, male reproductive health effects, developmental toxicities, human demographic characteristics or lifestyle factors such as dietary patterns. A few studies used the bioactivities to check the coverage of the chemical analyses of the human samples, whereas in vitro assays have so far not regularly been used for identifying CECs in human samples, but rather in environmental matrices or food packaging materials.
A huge field of novel applications using receptor-based in vitro assays for mixture toxicity assessment on human samples and effect-directed analysis (EDA) using high resolution mass spectrometry (HRMS) for identification of toxic compounds waits for exploration. In the future this could lead to a paradigm shift in the way we unravel adverse human health effects caused by chemical mixtures.
Fertility status may predict later mortality, but no studies have examined the effect of semen quality on subsequent mortality. Men referred to the Copenhagen Sperm Analysis Laboratory by general ...practitioners and urologists from 1963 to 2001 were, through a unique personal identification number, linked to the Danish central registers that hold information on all cases of cancer, causes of death, and number of children in the Danish population. The men were followed until December 31, 2001, death, or censoring, whichever occurred first, and the total mortality and cause-specific mortality of the cohort were compared with those of all age-standardized Danish men or according to semen characteristics. Among 43,277 men without azospermia referred for infertility problems, mortality decreased as the sperm concentration increased up to a threshold of 40 million/mL. As the percentages of motile and morphologically normal spermatozoa and semen volume increased, mortality decreased in a dose-response manner (Ptrend < 0.05). The decrease in mortality among men with good semen quality was due to a decrease in a wide range of diseases and was found among men both with and without children; therefore, the decrease in mortality could not be attributed solely to lifestyle and/or social factors. Semen quality may therefore be a fundamental biomarker of overall male health.
•Medical treatment for 12 weeks reduced serum PFOS by 60 % in a randomized cross-over study in a highly exposed population.•Serum concentrations of all measured PFAS decreased significantly in the ...treatment period.•Findings may offer a potential treatment to especially vulnerable, highly exposed populations.
Per- and polyfluoroalkyl substances (PFAS) are heat and stain resisting chemicals. They are persistent, bioaccumulating and spread ubiquitously. Many hotspots where humans are exposed to high levels of PFAS have been reported. A few small observational studies in humans suggest that treatment with an Anion Exchange Resin (AER) decreases serum PFAS. This first clinical controlled crossover study aimed to assess whether AER decreases perfluorooctanesulfonic acid (PFOS) in highly exposed adults.
An open label 1:1 randomized treatment sequence crossover study with allocation to oral AER (cholestyramine 4 g three times daily) or observation for 12 weeks was conducted among citizens from a PFAS hotspot. Main inclusion criteria was serum PFOS > 21 ng/mL. Primary endpoint was change in serum PFOS levels between treatment and observational period.
In total, 45 participants were included with a mean age of 50 years (SD 13). Serum PFOS baseline median was 191 ng/mL (IQR: 129–229) and decreased with a mean of 115 ng/mL (95 % CI: 89–140) on treatment, and 4.3 ng/mL in observation period corresponding to a decrease of 60 % (95 % CI: 53–67; p < 0.0001). PFHxS, PFOA, PFNA and PFDA decreased during treatment between 15 and 44 %. No serious adverse events were reported.
Oral treatment with AER significantly lowered serum PFOS concentrations suggesting a possible treatment for enhancing elimination of PFOS in highly exposed adults.
INTRODUCTIONExposure to perfluoroalkyl substances (PFAS) has been associated with lower bone mineral density (BMD) in animal and human studies, but prospective data from children are ...limited.OBJECTIVESTo determine associations between prenatal and early postnatal PFAS exposure and BMD at age 7 years.METHODSIn the Odense Child Cohort, Denmark, pregnant women were recruited in 2010-2012, and their children were invited for subsequent health examinations. At 12 weeks of gestation the pregnant women delivered a serum sample, and at age 18 months serum was obtained from the child to measure perfluorooctane sulfonic acid(PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) by LC-MS/MS. At age 7 years DXA scans were performed to measure bone mineral content (BMC) and BMD Z-score. PFAS in pregnancy (n = 881) and/or at age 18 months (n = 668) were regressed against DXA measurements, adjusted for maternal education, child height Z-score, sex (for BMC) and for postnatal exposure, additionally duration of total breastfeeding. We additionally performed structural equation models determining combined effects of pre-and postnatal PFAS exposures.RESULTSHigher prenatal and early postnatal serum concentrations of all measured PFAS were associated with lower BMC and BMD Z-scores at age 7 years, all estimates were negative although not all significant. For each doubling of 18-month exposure to PFNA or PFOS, BMD Z-scores were lowered by -0.10 (95 % CI -0.19;-0.00) and -0.08 (-0.17;-0.00), respectively after adjustment. Pre- and postnatal PFAS were correlated, but structural equation models suggested that associations with BMD were stronger for 18-month than prenatal PFAS exposure.DISCUSSIONBone density is established in childhood, and a reduction in BMD during early childhood may have long-term implication for peak bone mass and lifelong bone health. Future studies of the impact of PFAS exposure on fracture incidence will help elucidate the clinical relevance.
Objective To evaluate whether circulating levels of antimüllerian hormone (AMH) predict fecundability in young healthy women. Design Prospective cohort study. Setting General community. Patient(s) A ...total of 186 couples who intended to discontinue contraception to become pregnant were followed until pregnancy or for six menstrual cycles. Intervention(s) None. Main Outcome Measure(s) Fecundability was evaluated by the monthly probability of conceiving (i.e., fecundability ratio FR). In addition, circulating levels of LH, FSH, T, and sex hormone-binding globulin (SHBG) were evaluated in 158 of 186 women. Result(s) Fifty-nine percent of couples conceived during the study period. Compared to the reference group of women with medium AMH (AMH quintiles 2–4), fecundability did not differ significantly in women with low AMH (AMH quintile 1) (FR 0.81; 95% confidence interval CI 0.44–1.40). In contrast, women with high AMH (AMH quintile 5) had reduced fecundability (FR 0.62; 95% CI 0.39–0.99) after adjustment for covariates (woman's age, body mass index BMI, smoking, diseases affecting fecundability, and oligozoospermia). Irregular menstrual cycles were more prevalent in women with high AMH compared with women with low or medium AMH levels, and they had higher levels of LH (geometric mean: 8.4 vs. 5.3 IU/L) and LH:FSH ratio (2.4 vs. 1.8). After exclusion of women with irregular cycles, women with high AMH still had reduced fecundability (FR 0.48; 95% CI 0.27–0.85) and elevated LH:FSH ratio (2.4 vs. 1.7). Conclusion(s) Low AMH in healthy women in their mid-20s did not predict reduced fecundability. Even after exclusion of women with irregular cycles, the probability of conceiving was reduced in women with high AMH.
ObjectivesConsiderable interest and controversy over a possible decline in semen quality during the 20th century raised concern that semen quality could have reached a critically low level where it ...might affect human reproduction. The authors therefore initiated a study to assess reproductive health in men from the general population and to monitor changes in semen quality over time.DesignCross-sectional study of men from the general Danish population. Inclusion criteria were place of residence in the Copenhagen area, and both the man and his mother being born and raised in Denmark. Men with severe or chronic diseases were not included.SettingDanish one-centre study.Participants4867 men, median age 19 years, included from 1996 to 2010.Outcome measuresSemen volume, sperm concentration, total sperm count, sperm motility and sperm morphology.ResultsOnly 23% of participants had optimal sperm concentration and sperm morphology. Comparing with historic data of men attending a Copenhagen infertility clinic in the 1940s and men who recently became fathers, these two groups had significantly better semen quality than our study group from the general population. Over the 15 years, median sperm concentration increased from 43 to 48 million/ml (p=0.02) and total sperm count from 132 to 151 million (p=0.001). The median percentage of motile spermatozoa and abnormal spermatozoa were 68% and 93%, and did not change during the study period.ConclusionsThis large prospective study of semen quality among young men of the general population showed an increasing trend in sperm concentration and total sperm count. However, only one in four men had optimal semen quality. In addition, one in four will most likely face a prolonged waiting time to pregnancy if they in the future want to father a child and another 15% are at risk of the need of fertility treatment. Thus, reduced semen quality seems so frequent that it may impair the fertility rates and further increase the demand for assisted reproduction.
Perfluoroalkyl substances (PFAS) are persistent chemicals used in everyday consumer products leading to ubiquitous human exposure. Findings of impaired neurodevelopment after prenatal exposure to ...PFAS are contradictory and few studies have assessed the impact of postnatal PFAS exposure. Language development is a good early marker of neurodevelopment but only few studies have investigated this outcome separately. We therefore investigated the association between prenatal and early postnatal PFAS exposure and delayed language development in 18 to 36-month-old Danish children.
The Odense Child Cohort is a large prospective cohort. From 2010 to 2012 all newly pregnant women residing in the Municipality of Odense, Denmark was invited to participate. Concentration of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) were assessed in maternal serum collected in the 1st trimester of pregnancy and in child serum at 18 months. Parents responded to the Danish adaption of the MacArthur-Bates Communicative Development Inventories (MB-CDI) when their child was between 18 and 36 months. Language scores were converted into sex and age specific percentile scores and dichotomized to represent language scores above or below the 15th percentile. We applied Multiple Imputation by Chained Equation and conducted logistic regressions investigating the association between prenatal and early postnatal PFAS exposure and language development adjusting for maternal age, pre-pregnancy BMI, education and respectively fish intake in pregnancy or childhood and duration of breastfeeding in early postnatal PFAS exposure models.
We found no significant associations between neither prenatal nor early postnatal PFAS exposure and language development among 999 mother-child pairs.
In this low-exposed cohort the finding of no association between early postnatal PFAS exposure and language development should be interpreted with caution as we were unable to separate the potential adverse effect of PFAS exposure from the well documented positive effect of breastfeeding on neurodevelopment. We, therefore, recommend assessment of child serum PFAS at an older age as development of the brain proceeds through childhood and even a small impact of PFAS on neurodevelopment would be of public health concern at population level due to the ubiquitous human exposure.
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