Interaction between mother-fetus exposure to environmental toxicants and risk for abnormal development

Numerous research studies indicate that exposure to environmental contaminants can cause long term health risks especially during fetal development and/or early childhood. Several Persistent Organic Pollutants (POPs) such as perfluorinated chemicals (PFCs), organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) cross the placenta barrier and/or reach the newborn child via the mother’s breast milk. The strong correlation between PFC/POP levels in maternal blood during pregnancy and cord blood are indicative of the potential risk to the developing fetus.

Some of these POPs are “Endocrine Disrupting Compounds (EDCs)” due to their capacity to interfere with the hormonal and endocrine systems. The EDCs include compounds such as OCPs, PCBs and polychlorinated dibenzo-p-dioxins / dibenzo-furans (PCDDs/PCDFs). Population based studies show that serum POP mixtures ex vivo elicit hormone disruption. POPs including PFCs are suspected to be fetotoxic chemicals and recent studies suggest harmful effects on prenatal and childhood development such as fetal growth and neuropsychological functioning in children.

Furthermore, prenatal and childhood exposure to background levels of PCBs, PCDDs/PCDFs and heavy metals like mercury, lead, cadmium, manganese and arsenic was suggested to have adverse effects on neuropsychological functioning in children. Inverse associations have been reported between prenatal and postnatal exposure to PCBs, PCDDs/PCDFs as well as heavy metals and birth outcomes such as birth weight, head circumference, and growth rate. Furthermore, a recent Danish study showed an indication of an inverse correlation between total developmental score of the infant and maternal serum dioxin-like activity.

An emerging body of research provides evidence of decreased fecundity and fetal development and adverse neurobehavioral consequences resulting from prenatal and postnatal exposure to relatively low levels of OCPs and/or organophosphate pesticides in infants and children.

PFCs are a large group of chemicals used since the 1950’s in different industrial and commercial applications (e.g. Teflon, carpets, furniture, food stuff packing etc.). The perfluoroalkyl acids (PFAAs) include the perfluorocarboxylated acids (PFCAs) and perfluorosulfonated acids (PFSAs), and the PFAAs include the two most studied PFCs: the perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). These two compounds are the most studied because existing laboratory procedures in the past did not allow analyses of other PFCs that exist in lower concentrations. PFOA and PFOS are persistent in the environment and found in human blood, breast milk and liver with half lives of 4 to 10 years. In addition to studying these two PFCs, we will include 15 other PFC congeners providing more independent analyses of the potential PFC (neuro)-toxicity early in life. The PFCs are found globally and governmental regulations in USA and Europe on use and production of specific compounds such as PFOS and PFOA have been made. Recently, PFOS has been added to Annex B of the Stockholm Convention on POPs.

Based on animal studies PFOS and PFOA are suggested to be included in the group of POPs known to be developmental neurotoxicants. Neonatal exposure of mice to PFOS and PFOA affected the cholinergic system, manifested as hypoactive responses similar to developmental neurotoxic effects reported for PCBs.

Data from the DNBC show maternal perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) (the two most studied PFCs) levels to be associated with various reproductive and child health outcomes. Maternal levels of PFOA in early pregnancy were inversely associated with birth weight and smaller abdominal circumference and head circumference. Similar non-significant associations for PFOS were found. Follow-up studies up to 18 month of age indicate persistent growth restrictions. Moreover, DNBC studies also showed that PFCs may impact maternal fecundity.

Newborn size and the balance of macronutrients in pregnant women's diets are associated. Trace elements such as Selenium (Se) and zinc are of fundamental importance to human health. Se has antioxidant, anti-inflammatory and chemo-preventive properties and both maternal and offspring supplementations are essential for the antioxidant protection of the offspring at the time of birth. Maternal Se deficiency results in offspring growth retardation in animals, and deficiency of the essential micronutrient zinc can have adverse effects on physical growth and neurodevelopment of the child. Maternal lifestyle factors such as alcohol consumption and smoking during pregnancy can contribute to the adverse developmental effects of the fetus, and might act as confounders on the hypothesized effects of PFCs/POPs on pregnancy outcomes.

The overall goal of FETOTOX is to investigate whether exposure to PFCs/POPs during pregnancy affects fecundity of the mother, fetal and early child development including the risk of ASD, ADHD and CP.

The specific aims are
1) to develop a systematic monitoring program on time trend levels of PFCs/POPs among nulliparous pregnant women in Denmark through laboratory networks with strong quality assurance and control (QA/QC) protocols,
2) to develop tools for epidemiological and mechanistic bioeffect monitoring by exploring toxicological mechanisms,
3) to determine whether trace elements and antioxidants can counteract oxidative cellular stresses of POPs,
4) to estimate the effects of PFCs/POPs on fetal and infant growth, subfecundity and the risk of neuro-developmental delay,
5) to do case-cohort studies on potential associations between PFC levels in the mothers and ASD, ADHD and CP of the child,
6) to compare birth cohort exposures and fetal outcomes in Denmark, Norway, Greenland, and China.