PCBs alter rat hormones, organs in two generations.

What did they do?

This laboratory study using female rats examined if and how low level PCB exposure during development affects reproduction and fertility in multiple generations. The University of Texas research team mimicked human PCB exposure levels.

First, female rats were exposed to PCBs on critical days of pregnancy (days 16 and 18) when hormones influence the changing brain to become either male or female. Second, animals were exposed to a mixture of PCBs (commercially known as Aroclor 1221) commonly found in the environment. Third, relevant and very low levels (0.1, 1, or 10 milligrams per kilogram) of PCBs were tested.

Each pregnant rat (F0 or ‘mother’) exposed to PCBs gave birth to about 12 offspring (first generation, F1, or ‘daughters’). When these daughters matured, they were mated to produce the second generation (F2 or ‘granddaughters’).

The mothers (F0) were directly exposed to PCBs. The daughters (F1) were not directly exposed but instead were exposed through their mother's womb during development and via nursing after birth. The granddaughters (F2) were also never directly exposed, but were exposed indirectly during their mothers development, as females make at conception and carry through her life all of the eggs she will use during her reproductive years.

The authors' assessed reproductive health and fertility in both the daughters (F1) and the granddaughters (F2). They established developmental status through litter size, male-to-female sex ratio and weight. They measured the reproductive hormones luteinizing hormone, estradiol and progesterone in blood samples.

What did they find?

Overall, prenatal exposure to the low concentrations affected the long-term reproductive health of the female offspring rather than producing toxic or dramatic developmental problems.

More females than males were born in each post-exposed generation (children and grandchildren). Statistically, each generation alone was not significant but that changed when both generations were considered together. In that comparison, there was a significant trend toward more females when compared with control populations.

The daughters of PCB-exposed mothers had modest reproductive changes, including slightly increased body weight and higher luteinizing hormone levels. Both effects were found at the intermediate PCB dose tested (1 mg/kg).

More pronounced reproductive changes were found in the grandchildren of PCB-exposed mothers. The grandsons were heavier in the mothers exposed to the high PCB dose (10 mg/kg). The granddaughters had smaller uterine tissues and ovarian tissues.

Hormonal changes were seen in grandaughters at a critical period of reproduction called proestrus. During normal proestrus, high levels of luteinizing hormone and progesterone are required to ensure fertility. Here, at proestrus, the granddaughters had muted levels of both luteinizing hormone (approximately 10 times lower) and progesterone (about 3 times lower). These results strongly suggest that reproductive potential is compromised in the granddaughters.

What does it mean?

In their own words, the authors' find that "low levels of exposure to PCBs during late fetal development cause significant consequences on the maturation and physiology of two generations of female offspring."

This is one of the first studies to indicate that a low dose PCB exposure to a pregnant female will affect reproductive health and fertility in at least two generations, which is consistent with effects found with other endocrine disrupting chemicals.

The hormone and reproductive cycle changes observed in the study appear to be permanent and do worsen with each succeeding generation.

Exposure levels used were similar to what humans and wildlife experience. Similar effects in people and animals would mean the known and documented reproductive effects of PCBs could continue well into future generations. Although PCBs are now banned, their use peaked between 1950 and 1970. As such, the daughters, granddaughters and maybe even great-granddaughters of mothers exposed during that era may continue to be affected.

PCB-exposed rats gave birth to more female children and grandchildren than the unexposed mothers. Although the statistical power associated with this finding was weak, more and more studies on laboratory rats, fish and wildlife -- and even humans -- are reporting that industrial chemicals are skewing sex ratios and favoring females.

This study uses a dose response method to discern the multigenerational changes from PCB exposures in the womb. The hormone levels and developmental changes seen in the daughters, as compared to the controls, occurred at a mid range dose of 1 mg/kg.

These findings support the idea that endocrine-disrupting chemicals act in a non-monotonic manner and create U-shaped dose response curves. The middle dose had more effects than the higher and lower doses, which suggests all chemicals should be tested at various levels to ensure true safe limits of exposure.

The underlying mechanism of how PCBs change the hormone system to ultimately alter reproduction is not understood. Here, the authors hypothesize that PCBs may affect future reproduction by damaging the female germline (eggs and sperm), disrupting the regulation of genes important in reproduction or causing long-term changes to hormones.

A big concern is if other long lived chemicals may act in similar ways as PCBs to affect reproduction and fertility of future generations. For example, PBDEs (widespread flame retardant chemicals) have similar structures and properties to PCBs. PBDEs are rapidly polluting our environment but their long-term health effects are not yet known.