Pesticide exposure: the hormonal function of the female reproductive system disrupted?

Subfertility is defined as the inability to conceive within 12 months of regular, unprotected sexual intercourse and affects about 10 – 15% of all couples in the Western world [15]. A World Health Organization (WHO) multi-centre study revealed that the problem was predominantly male in 20% of subfertile couples and predominantly female in 38% of the cases, whereas 27% showed abnormalities in both man and woman and no evident cause of subfertility was identified in the remaining 15% [16]. Five types of subfertility disorders are distinguished [17].

Pesticides are used in agriculture and public health to control insects, weeds, animals, and vectors of disease. The Food and Agriculture Organization of the United Nations (FAO) defined a pesticide as 'any substance or mixture of substances intended for preventing, destroying or controlling any pest, including vectors of human or animal disease, unwanted species of plants or animals causing harm or otherwise interfering with the production, processing, storage, transport, or marketing of food, agricultural commodities, wood, wood products or animal feedstuffs, or which may be administered to animals for the control of insects, mites/spider mites or other pests in or on their bodies' [22]. Next to these intended effects, pesticides may also have adverse health effects for human beings. The main adverse health effects are difficulty in breathing, headaches, neurological or psychological effects, irritation of skin and mucous membranes, skin disorders, effects on the immune system, cancer, and reproductive effects. The manifestation of these effects depends on the type of pesticide and on level and duration of exposure. In this review, we will only focus on potential reproductive effects of pesticide exposure. Pesticides may cause reproductive toxicity through several different mechanisms: direct damage to the structure of cells, interference with biochemical processes necessary for normal cell function, and biotransformation resulting in toxic metabolites (see Figure 1). Reproductive effects that have been associated with pesticide exposure in women are decreased fertility, spontaneous abortions, stillbirth, premature birth, low birth weight, developmental abnormalities, ovarian disorders, and disruption of the hormonal function [23, 24]. Pesticides that may disrupt the hormonal function are often called endocrine disrupting chemicals (EDCs), just like other agents with similar mechanisms of action. An ECD may be defined as an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behaviour [21, 25]. Endocrine disruptors are usually either natural products or synthetic chemicals that mimic, enhance (agonists), or inhibit (antagonists) the action of endogenous hormones [25]. Body burden, dose, timing, and duration of exposure at critical periods in life are important considerations for assessing the risk of an adverse effect of endocrine disruptors. In the next paragraphs, we will review the ways in which pesticides may disrupt the female hormonal function of the reproductive system on the basis of experimental animal studies (in vivo) and cell culture studies (in vitro), which often provide the first indications of potential reproductive effects (see Table 1). We only describe possible mechanisms of disruption mentioned in the literature to indicate hazards, without judgement about human risks based on dose-response relations.

The function of the female reproductive system depends upon hormone concentrations and their balance. Endocrine disruption may result in disturbances in the reproductive system, such as modulation of hormone concentrations, ovarian cycle irregularities, and impaired fertility [91], which may be due to any of the mechanisms mentioned above. In many studies addressing these disturbances, however, the mechanisms are not specified. These studies, describing the effects of endocrine disrupting pesticides on the female reproductive system in more general terms, are summarized below (see also Table 1). As the majority of these studies are experimental animal studies, one should keep in mind that the estrus cycle in animals only partly corresponds with the ovarian cycle in humans, but that the phases (proestrus, estrus, metestrus, and diestrus) are different. Estrus is the period of greatest female sexual responsiveness usually coinciding with ovulation. Diestrus is the luteal phase of the estrus cycle when the female is not receptive to the male and the progesterone levels are high.

The studies described in the previous paragraphs are mostly studies involving laboratory animals (in vivo) or cell cultures (in vitro). Animal and in vitro studies are widely used and are often the first indicators of potential reproductive or developmental effects. However, the health risks for human populations may be considerably different, because of differences in exposure levels [128], reproductive issues, metabolism, size, and lifespan, which make it difficult to extrapolate from effects found in animals to effects that might be expected in women [23]. Recognising that a pesticide has the potential to cause harm reveals only a hazard. The risk of this pesticide actually inducing a biological effect depends on its properties, but the effect will only occur when exposure reaches a particular level [128]. Endocrine disruptors that accumulate in the body may eventually reach higher threshold levels necessary for exertion of their biological effects. Throughout the intricate processes of the menstrual cycle, ovum production, fertilization, implantation, and growth and developmental of the fetus, specific and often short time intervals exist in which these processes may be particularly susceptible to low-dose exposures of endocrine disruptors [23].

Another difficulty in human studies is that people can be exposed to endocrine disruptors in various ways, such as through iatrogenic exposure, endogenous estrogens, natural substances with estrogenic or androgenic activity (bioflavonoiden), and environmental endocrine disruptors like pesticides. In addition, it is quite feasible that interactions between endocrine disruptors play a role when there is combined exposure [129]. Therefore, the results of epidemiologic studies seldom pertain to specific pesticides and firm conclusions about causality of effects of endocrine disrupters on the female reproductive system are lacking. Still, we will give a quick overview of the epidemiological studies which found associations between pesticide exposure and reproductive effects that may be due to disruption of the female hormonal function (see Figure 1).