Indicators of microbial-rich environments and the development of papillary thyroid cancer in the California Teachers Study

Highlights

• First examination of early life exposures and later thyroid cancer development.

• We found significant associations with early exposure to hoofed animals and furry pets.

• Our findings are possibly consistent with the hygiene hypothesis for atopic disease.

Abstract

Background

Little epidemiologic research has focused on the role of immune function in papillary thyroid cancer risk despite scattered observations suggesting it may be important (e.g., hygiene hypothesis). Here we investigate papillary thyroid cancer risk associated with self-reported living environments across the lifespan reflecting immunologically relevant exposures to microbial-rich environments.

Methods

Among 61,803 eligible participants in the California Teachers Study cohort, 100 were diagnosed with invasive papillary thyroid cancer between 2005 and 2012. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI).

Results

Living in a rural area during early childhood was associated with significantly reduced risk of developing papillary thyroid cancer as an adult (HR = 0.51, 95% CI: 0.28–0.94). Specifically, reduced risks were observed for living within a half mile of hoofed animals (HR = 0.47, 95% CI: 0.26–0.84), as was having an indoor dog or cat (HR = 0.51, 95% CI: 0.32–0.80). Neither sharing a bedroom or living in a rented home as a child nor attending daycare or kindergarten was associated with reduced risk.

Conclusions

Early childhood exposures to hoofed animals or indoor furry pets were associated with reduced risk of subsequently developing papillary thyroid cancer.

Impact

Our findings point to immunologically relevant, early-life exposures to microbial-rich environments as potentially important in reducing thyroid cancer risk, consistent with the hygiene hypothesis and suggesting that certain, possibly animal-derived, microbial exposures may be important to immune calibration or priming.

Introduction

Thyroid cancer is currently the 5th most commonly diagnosed cancer in United States (US) women [1]. Substantial increases in incidence have been observed in US women and men across all ethnic groups [1], [2], [3]. With an average annual percent increase (AAPI) of 6.6% per year between 1996 and 2010 (compared to an AAPI of 2.5% between 1981 and 1996), incidence rates for thyroid cancer are increasing faster than those for any other cancer in women [1]. Improvements in diagnostic technology account for only a portion of the observed increase [2], [4], [5], [6]. Thus identifying new risk factors for thyroid cancer and understanding temporal changes in both established and new risk factors represent an increasingly important public health priority. At this time, the only well-established risk factors for the papillary (including the papillary/follicular variant) form of thyroid cancer (which comprises 80% of all thyroid cancer) are ionizing radiation, history of proliferative benign thyroid disease (BTD) (e.g., goiter and thyroid nodules), and family history of thyroid cancer or proliferative BTD [7], [8], [9]. However, these exposures have relatively low prevalence in the US [8], [10]. More recent studies have found obesity to increase risk [11], [12], [13] and the several years following a full-term pregnancy to be a period of high risk [14], [15]. Little research has focused on immunologic correlates of thyroid carcinogenesis despite the fact that half of all autoimmune diseases in women involve the thyroid [16]. These autoimmune diseases result from hyperactive cell-mediated immune responses against self-tissue [17], and women with autoimmune diseases such as systemic lupus erythematosus (SLE), are at significantly higher risk of developing thyroid cancer [18].

Given the rapid increase, environmental exposures relevant to immune function represent an understudied set of possible risk factors for thyroid cancer. During the last century we have seen unprecedented increases in persons living in more sterile environments and less crowded housing conditions, resulting in diminished exposure to a diversity of microbes [19]. This reduction in exposure to microbial-rich environments, especially when it occurs in early life, has been linked to hyperactive immune responses to allergens (e.g., atopic disease) in children and is thought to be detrimental to establishing the appropriate immune “calibration” or “priming” that may be needed for lifelong healthy immune function [19], [20], [21], [22]. This set of circumstances has been termed the “hygiene hypothesis.” Exposure to microbial-rich environments has been associated with lower risk of other cancers (e.g., daycare and childhood leukemia, occupational exposures to endotoxin-rich agricultural and textile environments and lung cancer [23], [24]) and it is plausible that similar exposures could be related to thyroid cancer development. Here we investigate the association between early life self-reported exposures to microbial-rich environments and papillary thyroid cancer risk in a large, prospective cohort of female California teachers.