Unpacking the Relationship Between Perfluoroalkyl Substances and Placental Hormones in Lactation.

Perfluoroalkyl substances (PFAS) are a class of degradation-resistant chemicals found in fire-fighting foams, industrial surfactants, and oil- and water-resistant consumer items. They persist in the environment and have been shown to have endocrine-disrupting activity in the human body. In particular, exposure to elevated levels of PFAS has been fairly consistently linked to shorter breastfeeding duration across sociodemographically and geographically diverse populations, although the exact mechanisms are unclear (1-5). Prior work has speculated that PFAS may interfere with initiation of lactation or adversely impact either the quality or quantity of milk produced (1). Because placental hormones are critical in lactation (6), it is important to understand the influence that endocrine-disrupting chemicals such as PFAS have on these hormones as they support lactation.

Animal studies indicate that PFAS suppress prolactin and placental lactogen signaling, interfering with mammary epithelial cell growth and differentiation and milk production (1). Mice exposed to perfluorooctanoic acid (PFOA), one of the hallmark chemicals of the class, during pregnancy showed reduced mammary gland differentiation and delayed epithelial involution (1). These associations are consistent throughout the life course: among mice treated with PFOA in utero and as juveniles, greater exposure levels are associated with diminished mammary gland development (1). PFOA also affects lactogenesis because mice exposed to PFOA during pregnancy did not have milk-filled alveoli just before giving birth (1).

Recent research by Timmerman et al, Pregnancy exposure to perfluoroalkyl substances, prolactin concentrations and breastfeeding in the Odense Child Cohort (7), is timely and novel in that it explores these questions of mechanism among humans in a large and well-characterized cohort. Although the current study does not provide strong evidence that PFAS interfere with lactation via an influence on prolactin, it does lay a foundation for further elucidating the influence of PFAS on placental hormones in humans.

As the authors indicate, their null association may be due to the timing of prolactin sampling in this study (7). Prolactin increases markedly during pregnancy to aid in development of mammary tissue in preparation for lactation after childbirth. Postnatally, prolactin peaks about 30 minutes into a feed, with highest levels at night. The authors measured prolactin at median 12 and 29 weeks of gestation, but sampling at term or during lactation may represent a more accurate predictor of breastfeeding success. Further studies on the associations between PFAS exposure and prolactin levels at these critical time points may show a stronger association.

Likewise, timing of PFAS sampling may be important in more clearly illuminating any associations with prolactin because animal studies indicate timing of exposure is important in lactation outcomes (1). As the authors note, while they measured PFAS levels during pregnancy, much of mammary gland development occurs in utero, and early-life exposure to PFAS transplacentally, through human milk, or during adolescence, may play a stronger role in mechanisms of lactation than do pregnancy exposures (7). Evidence also exists that PFAS’ influence on mammary gland development persist transgenerationally because animal studies find that mammary gland alterations persist in the F2 generations (1). Although logistically challenging, a more precise study of the association between PFAS exposure and lactation success as mediated by mammary gland development would involve measurement of PFAS exposure prenatally, in the early postnatal period, in adolescence, and may even include assessment of PFAS exposure from previous generations.

The authors of the present research performed sensitivity analyses within a subset of women with risk factors for gestational diabetes (GDM) because research shows an association between PFAS exposure and elevated fasting glucose among women with GDM risk factors and an inverse relationship between prolactin and GDM (7). In fact, many pregnancy hormones, both placental and otherwise, are implicated in both metabolism and lactation, and their secretion and inhibition are governed by intricate feedback mechanisms related to glucose metabolism (6). Further research is needed to explore these relationships among PFAS exposure, metabolism, and the hormones governing both metabolism and lactation and to understand whether vulnerable subgroups of pregnant women, such as those at risk of GDM, may be at increased risk of adverse effects of PFAS exposure in pregnancy.

Alternatively, these findings potentially indicate that the relationship between PFAS and prolactin does not play a clinically relevant role in lactation success in humans. However, other placental hormones and mechanisms may be involved in or mediate the relationship between PFAS exposure and lactation success (6). Animal models show that treatment with PFOA during pregnancy results in cellular changes to the placenta that affect the expression of genes regulating hormone production, reducing levels of mouse placental lactogen and prolactin-like proteins (1), so other key placental hormones may be affected beyond prolactin, or the complex interplay among these hormones may be disrupted. The pituitary gland and hypothalamus are also implicated in the hormonal pathways determining mammary gland development and lactation (6), and both of these organs have been shown to be affected by PFAS in animal studies (8). Other proposed mechanisms supported by animal models, such as activation of the peroxisome proliferator-activated receptor alpha, which can impair lobular-alveoli development, or alterations in milk protein gene expression, affecting both milk quantity and quality, may override or mediate any influences that PFAS have on prolactin (1).

Although this study does not provide support for an association of PFAS with prolactin in this cohort, it is an important addition to the literature. The present study both solidifies our understanding of the association between PFAS exposure and reduced breastfeeding duration and begins to explore the mechanisms governing this association among humans. Future work exploring other placental hormones and other endocrine-disrupting chemical exposures is critical to understanding how potentially modifiable environmental factors may influence lactation.