Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy

Abstract

Dioxin-like compounds are endocrine disruptors. The effects of prenatal exposure to environmental levels of dioxins on immune function during infancy have not been clarified, although dioxins induce immunosuppression in offspring of animals. Moreover, human studies have not assessed the effects of gender- or congener-specific differences. The purpose of this study was to investigate the association between dioxin levels in maternal blood and the risk of infection and allergies in infancy. We examined 364 mothers and their infants enrolled in a Hokkaido Study on Environment and Children's Health between 2002 and 2005 in Sapporo, Japan. Relevant information was collected from a baseline questionnaire during pregnancy, medical records at delivery, and a follow-up questionnaire when the child was 18 months of age that assessed development of allergies and infections in infancy. Dioxin-like compound levels in maternal blood were measured with high-resolution gas chromatography/high-resolution mass spectrometry. Relatively higher levels of polychlorinated dibenzofuran were associated with a significantly increased risk of otitis media, especially among male infants (odds ratio=2.5, 95% confidence interval=1.1–5.9). Relatively higher levels of 2,3,4,7,8-pentachlorodibenzofuran were also associated with a significantly increased risk of otitis media (odds ratio=5.3, 95% confidence interval=1.5–19). However, we observed a weak association between dioxin-like compound levels and allergic symptoms in infancy. At environmental levels, prenatal exposure to dioxin-like compounds may alter immune function and increase the risk of infections in infancy, especially among males. The compound 2,3,4,7,8-pentachlorodibenzofuran may be responsible for this.

Introduction

Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL PCBs) are endocrine disruptors that persistently exist in the food chain and environment. These compounds are classified as dioxin-like compounds (DLCs) because of their similarities in structure and mechanism of toxicity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Yoshizawa et al., 2007). Humans are mainly exposed to DLCs through intake of contaminated animal products. DLCs are reported to accumulate mostly in adipose tissue over multiple years due to their high lipophilicity and resistance to biodegradation (Schecter and Gasiewicz, 2003). In humans, DLCs cross the placenta of pregnant women and are transferred to the fetal tissue and cord blood (Todaka et al., 2010).

Animal studies have demonstrated that fetal TCDD exposure inhibits cellular differentiation and maturation, particularly of T lymphocytes, causes thymic atrophy, and leads to immunosuppression in offspring (Yoshizawa et al., 2007). Offspring of maternal rats treated with TCDD during the third trimester have a greater sensitivity to immune toxicity induced by TCDD than adults, and the adverse effects that occur at critical windows of maturation persist later in life. In addition, male rat offspring may be more sensitive than females to TCDD-mediated suppression of T cell activity (Luebke et al., 2006). At comparable environmental levels, exposure to complex mixtures of DLCs may induce immunosuppression in both mice and humans (Smialowicz et al., 2008).

In the Taiwan Yucheng accident, children born to mothers who had accidentally ingested high levels of contaminated rice oil had higher frequencies of bronchitis, reduced serum levels of immunoglobulin (Ig) A, IgG, and IgM at 6 months (Yu et al., 1998), and a higher incidence of influenza and otitis media at 6 years of age than unexposed controls (Chao et al., 1997, Rogan et al., 1988). PCDFs, rather than PCBs, may be primarily responsible for the immunotoxicity related to Yucheng symptoms (Masuda, 2001). In Japan, infants born to mothers occupationally exposed to high levels of PCBs have a higher frequency of colds and gastrointestinal complaints (Hara, 1985). In Inuit infants born to mothers who had ingested high levels of contaminated marine mammals, higher prenatal PCB exposure led to a significantly elevated incidence of infections such as acute otitis and respiratory problems (Dallaire et al., 2004, Dallaire et al., 2006). On the Faroe Islands, PCB levels in maternal serum were inversely associated with an antibody response to diphtheria toxoid at 18 months of age and tetanus toxoid at 7 years of age (Heilmann et al., 2006). In an eastern Slovakia study, higher PCB levels in maternal serum were associated with newborns who had a smaller thymus, the organ responsible for lymphocyte maturation (Park et al., 2008).

A few human studies have addressed prenatal exposure to environmental levels of PCBs/dioxins, although several of these studies were conducted in populations exposed to high levels. In the Rotterdam study, PCBs in maternal blood and dioxins in breast milk were significantly associated with a higher prevalence of otitis media and chicken pox, as well as a lower prevalence of shortness of breath with asthma. In addition, these indicators were related to a reduction in measles, mumps, and rubella reactivity after primary vaccination and an increased number of T lymphocytes at 42 months (Weisglas-Kuperus et al., 2000, Weisglas-Kuperus et al., 2004). On the other hand, in the Amsterdam study, dioxin levels in breast milk were associated with decreased allergies but not with any infections at 8 years of age (ten Tusscher et al., 2003). In Spain, PCB levels in cord blood were not related to the prevalence of asthma at 4 years of age (Sunyer et al., 2005). In Japan, DLC levels in breast milk were significantly associated with an increased lymphocyte subset ratio in the peripheral blood of breast-fed infants at 10 months (Nagayama et al., 2007), but no association was observed in another cohort of Japanese infants at 12 months of age (Kaneko et al., 2006).

In environmentally exposed populations, data for associations between prenatal exposure to DLCs (with consequent immunosuppression) and increased incidence of infectious diseases are relatively consistent, although causality has never been established. In contrast, only a few studies have addressed allergies or asthma, and these findings appear controversial. In addition, human studies have yet to assess gender- or congener-specific differences regarding the effects of prenatal exposure to DLCs on allergies and infections in infancy, and have not used DLC levels in maternal blood as indicators of prenatal exposure.

The subjects of this study were recruited in the Hokkaido Study on Environment and Children's Health, which previously reported that environmental pollution levels in Sapporo were relatively lower than in other areas of Japan, Europe, and the USA (Konishi et al., 2009). Furthermore, it also reported that maternal DLC levels were inversely correlated with IgE levels in cord blood (Washino et al., 2007). These findings suggested that prenatal exposure to low levels of DLCs may affect immune function immediately after birth. The purpose of this study was to investigate the effects of prenatal exposure to DLCs on allergies and infections during the first 18 months of life.